GLYXAMBI tablets for oral use contain: empagliflozin and linagliptin. Empagliflozin Empagliflozin is an inhibitor of the 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 C 23 H 27 ClO 7 and the molecular weight is 450.91. The structural formula is: Empagliflozin is a 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 Linagliptin Linagliptin is an inhibitor of the 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 C 25 H 28 N 8 O 2 and the molecular weight is 472.54. The structural formula is: Linagliptin is a 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 GLYXAMBI GLYXAMBI tablets are available in two dosage strengths containing 10 mg or 25 mg empagliflozin in combination with 5 mg linagliptin. The inactive ingredients of GLYXAMBI are the following: Tablet Core: copovidone, corn starch, crospovidone, magnesium stearate, mannitol, pregelatinized starch, and talc. Coating: ferric oxide yellow (10 mg/5 mg) or ferric oxide red (25 mg/5 mg), hypromellose, mannitol, polyethylene glycol, talc, and titanium dioxide.

GLYXAMBI is a combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease . GLYXAMBI is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease. Limitations of Use Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. Has not been studied in patients with a history of pancreatitis. Not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 . Limitations of Use GLYXAMBI is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients . GLYXAMBI has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI . GLYXAMBI is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 . GLYXAMBI is likely to be ineffective in this setting based upon its mechanism of action.

GLYXAMBI tablets 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". Tablets: 10 mg empagliflozin/5 mg linagliptin 25 mg empagliflozin/5 mg linagliptin

Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. The recommended dosage of GLYXAMBI is 10 mg empagliflozin and 5 mg linagliptin once daily, taken in the morning, with or without food. Dosage may be increased to 25 mg empagliflozin and 5 mg linagliptin once daily. Withhold GLYXAMBI for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting

Testing Prior to Initiation of GLYXAMBI Assess renal function before initiating GLYXAMBI and as clinically indicated . Assess volume status. In patients with volume depletion, correct this condition before initiating GLYXAMBI

Recommended Dosage and Administration The recommended dosage 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

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 m 2

Temporary Interruption for Surgery Withhold GLYXAMBI for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake

Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible. Advise patients not to double up the next dose.

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk of ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue GLYXAMBI if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI. 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. Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections: Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue GLYXAMBI, and promptly institute appropriate medical and/or surgical intervention. Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI. Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. 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. Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. 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. 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. 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, empagliflozin, a component of GLYXAMBI, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. GLYXAMBI is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including GLYXAMBI. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing GLYXAMBI ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue GLYXAMBI, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting GLYXAMBI. Withhold GLYXAMBI, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue GLYXAMBI and seek medical attention immediately if signs and symptoms occur

Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial , 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

Volume Depletion Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine . There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), 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

Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections Empagliflozin increases urinary glucose excretion and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients . Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with or without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin . Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. GLYXAMBI is only indicated for use in patients with type 2 diabetes mellitus. Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using GLYXAMBI. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue GLYXAMBI and promptly institute appropriate medical and/or surgical intervention

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when GLYXAMBI is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI

Lower Limb Amputation In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95 % CI) (0.81, 1.36). In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations. GLYXAMBI is not indicated for the treatment of chronic kidney disease. Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving GLYXAMBI for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment

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 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 empagliflozin. 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 hypersensitivity to linagliptin, empagliflozin or any of the excipients in GLYXAMBI

Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. 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 DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate

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 , 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

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.

Table 3 describes clinically relevant interactions with GLYXAMBI. Table 3 Clinically Relevant Interactions with GLYXAMBI Diuretics Clinical Impact Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion. Intervention Before 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 Secretagogues Clinical Impact The risk of hypoglycemia is increased when GLYXAMBI is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Intervention Coadministration of GLYXAMBI with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during GLYXAMBI initiation and dosage changes. Inducers of P-glycoprotein or CYP3A4 Enzymes Clinical Impact Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Intervention Use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring 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) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. See full prescribing information for information on drug interactions and interference of GLYXAMBI with laboratory tests.