`
`These highlights do not include all the information needed to use
`
`
` GLYXAMBI safely and effectively. See full prescribing information for
` GLYXAMBI.
`
`
`
` GLYXAMBI® (empagliflozin and linagliptin tablets), for oral use
` Initial U.S. Approval: 2015
`
`
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`
`
` Indications and Usage (1)
`
`
`
`
` Dosage and Administration (2.1, 2.3)
`
`
` Contraindications (4)
` Warnings and Precautions (5.2, 5.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6/2021
`
`
` 6/2021
`
` 6/2021
`
`
` 6/2021
`
`
`----------------------------INDICATIONS AND USAGE--------------------------
`
`
`
` 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 death in adults
`
`
` with type 2 diabetes mellitus and established cardiovascular disease. (1)
`
` Limitations of Use
`
`•
`
`
`
` Not recommended in patients with type 1 diabetes mellitus. It may
`
` increase the risk of diabetic ketoacidosis in these patients (1)
`
`
`
`
`
` Has not been studied in patients with a history of pancreatitis (1)
`
`
` 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 m2 (1)
`
`
`
`•
`
`•
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------
`•
`
`•
`
`
`
`
`
`
`
` Assess renal function before initiating and as clinically indicated (2.1)
`
` The recommended dose of GLYXAMBI is 10 mg empagliflozin and
`
`
`
` 5 mg linagliptin once daily, taken in the morning, with or without food
`
` (2.2)
`
` Dose may be increased to 25 mg empagliflozin and 5 mg linagliptin
`
`
` once daily (2.2)
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets:
`
`
`10 mg empagliflozin/5 mg linagliptin
`
`
`
`25 mg empagliflozin/5 mg linagliptin (3)
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`•
`
`•
`
`
`
`
` Patients on dialysis (4)
`
` Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in
` GLYXAMBI (4, 5.8)
`
`
`
`
`
`-----------------------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
`
`
`•
`
`
`
`
`
`
`Reference ID: 4810096
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
` 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 (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. (5.6)
`
`
` 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 a 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)
`
`
`
` ------------------------------ADVERSE REACTIONS------------------------------
`•
`
`
` 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.
`
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`•
`
`
`
`
`
`
`
` Pregnancy: Advise females of the potential risk to a 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)
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and Medication
`
` Guide.
`
`
`
`
`
`
`
`
`
`
`
`Revised: 6/2021
`
`
`
` 1
`
`
`
`
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`6.2 Postmarketing Experience
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` 7 DRUG INTERACTIONS
`
`
`
` INDICATIONS AND USAGE
`
`
`
`1
` 8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`2.1 Prior to Initiation of GLYXAMBI
`
`8.2 Lactation
`
`
`
`
`
`
`2.2 Recommended Dosage
`
`8.4 Pediatric Use
`
`
`
`
`
`2.3 Dosage Recommendations in Patients with Renal Impairment
`
`8.5 Geriatric Use
`
`
`
`
`
`
`
`8.6 Renal Impairment
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`8.7 Hepatic Impairment
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` 5 WARNINGS AND PRECAUTIONS
` 10 OVERDOSAGE
`
`5.1 Pancreatitis
`
`
`
`
` 11 DESCRIPTION
`
`5.2 Ketoacidosis
`
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
`5.3 Volume Depletion
`
`12.1 Mechanism of Action
`
`
`
`
`
`5.4 Urosepsis and Pyelonephritis
`
`12.2 Pharmacodynamics
`
`
`
`
`
`5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`12.3 Pharmacokinetics
`
`
`
`
`
`Secretagogues
`
`
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`
`5.7 Genital Mycotic Infections
`
`
`
`
` 14 CLINICAL STUDIES
`
`5.8 Hypersensitivity Reactions
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`5.9 Severe and Disabling Arthralgia
`
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`5.10 Bullous Pemphigoid
`
`
`
`
`5.11 Heart Failure
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
` 6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4810096
`
`
`
` 2
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
` 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 death in adults with type 2 diabetes mellitus and
`
` established cardiovascular disease [see Clinical Studies (14)].
`
`
`
` Limitations of Use
`
`
` GLYXAMBI is not recommended in patients with type 1 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 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
` [see Warnings and Precautions (5.1)].
`
`
` 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 m2. GLYXAMBI is likely to be ineffective in this setting based upon
`
` its mechanism of action.
`
`
`
`
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
`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)].
`
`•
`
`
`
`
`
`
`
`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 AND STRENGTHS
`
`
` 3
`
`
`
` GLYXAMBI tablets are a 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”.
`
`
`
`
`Reference ID: 4810096
`
`
`
` 3
`
`
`
`
` CONTRAINDICATIONS
`
`
` 4
`• 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)].
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`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 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.
`
`
`
`5.2 Ketoacidosis
`
`
`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been
`
` identified in clinical trials and 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. In placebo-controlled trials of patients with
`type 1 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 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,
`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.
`
`For patients who undergo scheduled surgery, consider temporarily discontinuing GLYXAMBI for at least 3
`
` days prior to surgery [see Clinical Pharmacology (12.2, 12.3)].
`
`
`
`
`
`
`Reference ID: 4810096
`
`
`
` 4
`
`
`
`
`
`
`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 2
`
`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 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.
`
` 5.6 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.
`
` 5.7 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.
`
`
`
`
`
`
`Reference ID: 4810096
`
`
`
` 5
`
`
`
`
`
`
`
`
` 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 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.
`
` 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 [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. 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.
`
`
` 5.10 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)], 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.
`
` 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 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.
`
`
`
`
`
` ADVERSE REACTIONS
` 6
`
`
` 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)]
`
`
`
`
`
`Reference ID: 4810096
`
`
`
` 6
`
`
`
`
`
`• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and
`
`
`Precautions (5.5)]
`
`
`• Necrotizing Fasciitis of the Perineum (Fournier’s 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)]
`
`
`
`
`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
`
`
`
`
`
`
` Adverse Reactions
`
`
`
`
`
` GLYXAMBI (%)
`
`
` GLYXAMBI (%)
` 25 mg/5 mg
`
` 10 mg/5 mg
`
` n=273
`
`
` n=272
`
` Urinary tract infectiona
`
` 11.4
`
` 12.5
`
` Nasopharyngitis
` 6.6
`
` 5.9
`
` Upper respiratory tract infection
`
` 7.0
`
` 7.0
`
`
` aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
`
` 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. Events related to volume depletion (hypotension and syncope) were
`
` reported in 3 patients (1.1%) treated with GLYXAMBI plus metformin.
`
` 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%).
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4810096
`
`
`
` 7
`
`
`
`
`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 Overalla and Severeb Hypoglycemic Adverse Reactions
`
`
`
`
`
`
`
`
`
`
`
` Add-on to Metformin
`
` (52 weeks)
`
`
`
` GLYXAMBI (%)
`
`
` GLYXAMBI (%)
` 25 mg/5 mg
`
` 10 mg/5 mg
`
`
`
` (n=137)
` (n=136)
`
` 3.6
`
` 2.2
`
` Overall
`
`
`
` Severe
` 0
` 0
` 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
`
`
` 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
`
` 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 a study of
` patients with moderate renal impairment, larger mean changes were observed. In a 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 a 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).
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4810096
`
`
`
` 8
`
`
`
`
`
` 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.
`
` Increase in Amylase: In a cardiovascular safety study comparing linagliptin versus glimepiride in patients with
`
`
`
`
`
` type 2 diabetes mellitus, amylase levels above 3 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 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
`
`
`• Acute Kidney Injury
`
`
`• Skin Reactions (e.g., rash, urticaria)
`
`
`• Mouth Ulceration, Stomatitis
`
`
`• Rhabdomyolysis
`
`
`
`
`
` DRUG INTERACTIONS
` 7
`
`
`
` 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
`
`
`
` 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.
`
`
`
`
`
` Intervention
`
`
`
` Coadministration 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
`
`
`
` Positive Urine Glucose Test
`
`
`
` hypoglycemia.
`
`
`
` Clinical Impact
`
`
`
` SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose
`
`
`
` tests.
`
`
`
`Reference ID: 4810096
`
`
`
` 9
`
`
`
`
`
` 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
`
`
`
` Inducers of P-glycoprotein or CYP3A4 Enzymes
`
`
`
` to monitor glycemic control.
`
`
`
` Clinical Impact
`
`Rifampin decreased linagliptin exposure, suggesting that the efficacy of linaglipt