`
`
`
` 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-------------------------
`
` 12/2017
`
`
`
`
`
` Contraindications (4)
`
` Warnings and Precautions (5)
`
`
`
`
` 12/2017
`
`
`
` ----------------------------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 when treatment with
`
`
`
`
`
` both empagliflozin and linagliptin is appropriate.
`
`
`
`
`
` Empagliflozin is indicated to reduce the risk of cardiovascular death in adults
` with type 2 diabetes mellitus and established cardiovascular disease.
`
`
`
`
`
`
` However, the effectiveness of GLYXAMBI on reducing the risk of
`
`
`
`
` cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular
`
`
` disease has not been established. (1)
`
`
`
`
`
`
` Limitations of use:
`
`Not recommended for patients with type 1 diabetes or for the treatment
`
`
`
`
`
`
`•
`of diabetic ketoacidosis (1)
`
`
`Has not been studied in patients with a history of pancreatitis (1)
`
`
`
`
`
`
`•
`----------------------DOSAGE AND ADMINISTRATION----------------------
`
`
`
`The recommended dose of GLYXAMBI is
`
`
`
`
`•
`10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning,
`
`
`
`with or without food (2.1)
`
`
`
`Dose may be increased to 25 mg empagliflozin/5 mg linagliptin once
`
`
`
`daily (2.1)
`
`Assess renal function before initiating GLYXAMBI. Do not initiate
`
`
`
`
` GLYXAMBI if eGFR is below 45 mL/min/1.73 m2 (2.2)
`
`
`
`
`
` Discontinue GLYXAMBI if eGFR falls persistently below 45
`
`
`
`
`
` mL/min/1.73 m2 (2.2)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`Tablets:
`
`
`10 mg empagliflozin/5 mg linagliptin
`
`
`
`
`25 mg empagliflozin/5 mg linagliptin (3)
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`
`
`Severe renal impairment, end-stage renal disease, or dialysis (4)
`
`
`
`
`•
`
`History of serious hypersensitivity reaction to empagliflozin, linagliptin,
`
`
`
`
`•
`or any of the excipients in GLYXAMBI such as anaphylaxis,
`
`
`
`
`
`angioedema, exfoliative skin conditions, urticaria, or bronchial
`
`
`
`
`hyperreactivity (4)
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
`
`Pancreatitis: There have been postmarketing 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)
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`Secretagogues
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`5.8 Genital Mycotic Infections
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`5.9 Hypersensitivity Reactions
`
`
`
`
`5.10 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`2.1 Recommended Dosage
`
`
`
`
`
`5.11 Severe and Disabling Arthralgia
`2.2 Patients with Renal Impairment
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`5.12 Bullous Pemphigoid
`
`
`
`4 CONTRAINDICATIONS
`
`5.13 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`6.1 Clinical Trials Experience
`5.1 Pancreatitis
`
`
`
`
`6.2 Postmarketing Experience
`5.2 Heart Failure
`
`
`
`7 DRUG INTERACTIONS
`
`5.3 Hypotension
`
`
`
`7.1 Drug Interactions with Empagliflozin
`5.4 Ketoacidosis
`
`
`
`
`
`
`7.2 Drug Interactions with Linagliptin
`5.5 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`5.6 Urosepsis and Pyelonephritis
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`Revised: 12/2017
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`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)
`
`Genital Mycotic Infections: Monitor and treat as appropriate (5.8)
`
`
`
`Hypersensitivity Reactions: Discontinue GLYXAMBI, treat promptly,
`
`
`
`
`
`and monitor until signs and symptoms resolve. (5.9)
`
`
`Increased LDL-C: Monitor and treat as appropriate (5.10)
`
`
`
`
`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. (5.11)
`
`
`
`
`Bullous Pemphigoid: There have been postmarketing reports of bullous
`
`
`
`
`
`pemphigoid requiring hospitalization in patients taking DPP-4
`
`inhibitors. Tell patients to report development of blisters or erosions. If
`
`
`
`
`
`
`
`bullous pemphigoid is suspected, discontinue GLYXAMBI. (5.12)
`
`
`
`
`
`• Macrovascular Outcomes: There have been no clinical studies
`
`
`
`
`establishing conclusive evidence of macrovascular risk reduction with
`
`
`
`GLYXAMBI. (5.13)
`
`------------------------------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 1-800-459-9906
`
`
`TTY, 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 (5.2, 5.4, 8.5)
`
`
`
`Renal Impairment: Higher incidence of adverse reactions related to
`
`
`
`
`reduced renal function (2.2, 5.4, 8.6)
`
`
`
`
`
`
`Reference ID: 4195044
`
`
`
` 1
`
`
`
`
`
`
`
`
`
`
`
` 8.1 Pregnancy
`
` 8.2 Lactation
`
`
`
` 8.4 Pediatric Use
`
`
` 8.5 Geriatric Use
`
`
` 8.6 Renal Impairment
`
` 8.7 Hepatic Impairment
` 10 OVERDOSAGE
`
`
` 11 DESCRIPTION
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`
`
`
`
`14.1 GLYXAMBI Glycemic Control Studies
`
`
`
`
`
`
`14.2 Empagliflozin Cardiovascular Outcome Study in Patients with
`
`
`
`Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular
`
`
`Disease
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`
`
`
`Reference ID: 4195044
`
`
`
` 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 when treatment with both empagliflozin and
`
`
`
`
` linagliptin is appropriate.
`
`
`
`
`
`
` Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and
` established cardiovascular disease [see Clinical Studies (14.2)]. However, the effectiveness of GLYXAMBI on
`
`
`
`
`
` reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has
`
`
`
`
`
`
`
`
` not been established.
`
`
`
` Limitations of Use
`GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis
`
`
`
`
`
`
`
`
`
`[see Warnings and Precautions (5.4)].
`
`
`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)].
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`2.1 Recommended Dosage
`
`The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning,
`
`
`
`
`taken with or without food. In patients tolerating GLYXAMBI, the dose may be increased to 25 mg
`
`
`
`
`empagliflozin/5 mg linagliptin once daily.
`
`
`
`In patients with volume depletion, correcting this condition prior to initiation of GLYXAMBI is recommended
`
`
`
`
`
`[see Warnings and Precautions (5.3), Use in Specific Populations (8.5) and Patient Counseling Information
`(17)].
`
`
`No studies have been performed specifically examining the safety and efficacy of GLYXAMBI in patients
`
`
`
`
`
`
`
`
`previously treated with other oral antihyperglycemic agents and switched to GLYXAMBI. Any change in
`
`
`
`therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic
`
`
`
`
`
`
`control can occur.
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`Assessment of renal function is recommended prior to initiation of GLYXAMBI and periodically thereafter.
`
`
`
`
`
`
`
`
`GLYXAMBI should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
`
`
`
`
`
`
` No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
`
` GLYXAMBI should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and
`
`
`
`
`
`Precautions (5.3, 5.5) and Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4195044
`
`
`
` 3
`
`
`
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
`
`
` GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following
`
`
` dosage forms and strengths:
`
`
`
`
`
`
`
`
`
` • 10 mg empagliflozin/5 mg linagliptin tablets 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 tablets 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”.
`
`
`
` 4
`
`
` CONTRAINDICATIONS
` GLYXAMBI is contraindicated in patients with:
`
`
`
`
`
`
`
` • Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].
`
`
`
` • A history of serious hypersensitivity reaction to empagliflozin, linagliptin, or any of the excipients in
`
`
`
`
`
`
`GLYXAMBI such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial
`
`
`
`
`
`
`hyperreactivity [see Warnings and Precautions (5.9) and Adverse Reactions (6)].
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Pancreatitis
`
`There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking
`
`
`
`
`
`
`
` Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected,
`linagliptin.
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`Reference ID: 4195044
`
`
`
` 4
`
`
`
`
`
`
`
`
`
` 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 (5.1)] 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,
`
`
`
`
`
`
`
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`
` discontinue GLYXAMBI promptly and institute treatment.
`
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`
`
` 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 m2. Use of GLYXAMBI is not recommended when eGFR is persistently less than 45
`
`
`
`
`
`mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and
`
`
`
`
`Administration (2.2), Contraindications (4) and Use in Specific Populations (8.6)].
`
`
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis
`
`
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`
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`requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with
`
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`Reference ID: 4195044
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` 5
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`
`
` 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
`
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`
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`
`
` The use of empagliflozin or linagliptin in
` Insulin and insulin secretagogues are known to cause hypoglycemia.
` 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
`
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`
`
` insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
`
`
`
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`
`
`5.8 Genital Mycotic Infections
`
`
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`
`
`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.
`
`
`
`5.9 Hypersensitivity Reactions
`
`
`
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin
`
`
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`
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`(one of the components of GLYXAMBI). These reactions include anaphylaxis, angioedema, and exfoliative
`
`
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`
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`skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with
`
`
`
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`linagliptin, with some reports occurring after the first dose.
`
`
`
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`
`
`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
`
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`until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with a previous serious
`
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`
`hypersensitivity reaction to linagliptin or empagliflozin [see Contraindications (4)].
`
`
`5.10 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.
`
`
`5.11 Severe and Disabling Arthralgia
`
`
`
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors.
`
`
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`
`
`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
`
`
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`
`
`recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider as a possible
`
`
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`
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`cause for severe joint pain and discontinue drug if appropriate.
`
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`
`
`5.12 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
`
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`discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while
`
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`
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`receiving GLYXAMBI. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued and referral
`
`
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`
`to a dermatologist should be considered for diagnosis and appropriate treatment.
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`Reference ID: 4195044
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` 6
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` 5.13 Macrovascular Outcomes
`
`
`
`
` There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
` GLYXAMBI.
`
` 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)]
`
`
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` • Genital Mycotic Infections [see Warnings and Precautions (5.8)]
`
`
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.9)]
`
`
` Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.10)]
`
`
`•
`
` • Severe and Disabling Arthralgia [see Warnings and Precautions (5.11)]
`
`
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` • Bullous Pemphigoid [see Warnings and Precautions (5.12)]
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`6.1 Clinical Trials Experience
`
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`
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`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
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`
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`reflect the rates observed in practice.
`
`
`Empagliflozin and Linagliptin
`
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`The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose
`
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`5 mg) has been evaluated in a total of 1363 patients with type 2 diabetes treated for up to 52 weeks in active-
`
`
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`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
`
`
`
`
`
`
`
` GLYXAMBI
`
`
` GLYXAMBI
`
`
` 10 mg/5 mg
`
` 25 mg/5 mg
`
`
` n=272
` n=273
`
` n (% )
`
` n (% )
`
`
` Urinary tract infectiona
`
`
` 34 (12.5)
` 31 (11.4)
`
`
` 18 (6.6)
`
` 16 (5.9)
` Nasopharyngitis
` Upper respiratory tract infection
`
` 19 (7.0)
`
` 19 (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
`
`
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`
`
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` given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female
`
`
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` genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%),
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`
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` increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and
`
`
`
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`
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` 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).
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` 7
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`Reference ID: 4195044
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` 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
`
`
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`
`
`
`
` 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
`
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`
`
`
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`
`
`being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with
`
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`
`
` comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported
`
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`
` following the last administered dose of linagliptin.
`
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`
`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 Severe b Hypoglycemic Adverse Reactions
`
`
`
`
`
` GLYXAMBI
`
` GLYXAMBI
`
` Add-on to Metformin
`
`
`
`10 mg/5 mg
` 25 mg/5 mg
` (52 weeks)
`
` (n=137)
`
` (n=136)
`
`
` 3.6%
`
` 2.2%
`
` Overall (%)
`
` Severe (%)
`
`
` 0%
` 0%
` aOverall hypoglycemic events: plasma or capillary glucose ofless 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
`
`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 (5.10)]. 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%,
`
`
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`
`
`and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of
`
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`
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`the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
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`Reference ID: 4195044
`
`
`
` 8
`
`
`
`
` 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) and Warnings and
`
`
`
` Precautions (5.1)]
`
`
`
` • Ketoacidosis [see Warnings and Precautions (5.4)]
`
`
`
`
` • Urosepsis and pyelonephritis [see Warnings and Precautions (5.6)]
`
`
`
` • Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see
`
`
`
`Warnings and Precautions (5.9)]
`
` • Severe and disabling arthralgia [see Warnings and Precautions (5.11)]
`
`
` • Bullous pemphigoid [see Warnings and Precautions (5.12)]
`
`
` • Skin reactions (e.g., rash, urticaria)
`
`
`
` • Mouth ulceration, stomatitis
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` DRUG INTERACTIONS
` 7
`
`
`
` 7.1 Drug Interactions with Empagliflozin
` Diuretics
`
` Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids,
`
`
`
`
`
`
` which might enhance the potential for volume depletion [see Warnings and Precautions (5.3)].
`
` Insulin or