HIGHLIGHTS OF PRESCRIBING INFORMATION
`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--------------------------
`Warnings and Precautions
` 7/2019
`
`
`
` Pancreatitis (5.1)
`
` Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) (5.8) 10/2018
` Bullous Pemphigoid (5.13)
`
`
`
` 7/2019
` Macrovascular Outcomes – Removed
`
`
` 7/2019
`
`----------------------------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.
`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)
`•
`Hypersensitivity 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 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
`
`•
`
`
`
`
`
`
`
`Reference ID: 4457960
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`•
`
`•
`
`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)
`
`------------------------------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 (5.3, 5.5, 8.5)
`Renal Impairment: Higher incidence of adverse reactions related to
`reduced renal function (2.2, 5.5, 8.6)
`
`•
`•
`
`•
`
`•
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
`
`Revised: 7/2019
`
`1
`
`

`

`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`7.2 Drug Interactions with Linagliptin
`7.3
`Insulin or Insulin Secretagogues
`8 USE IN SPECIFIC POPULATIONS
`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
`14.3 Linagliptin Cardiovascular Safety Trial
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
` INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Patients with Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Heart Failure
`5.3 Hypotension
`5.4 Ketoacidosis
`5.5 Acute Kidney Injury and Impairment in Renal Function
`5.6 Urosepsis and Pyelonephritis
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues
`5.8 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`5.9 Genital Mycotic Infections
`5.10 Hypersensitivity Reactions
`5.11 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`5.12 Severe and Disabling Arthralgia
`5.13 Bullous Pemphigoid
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Drug Interactions with Empagliflozin
`
` 1
`
`
`
`
`
`
`
`
`Reference ID: 4457960
`
`2
`
`

`

`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`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 (14.2)]. 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)].
`
` 2
`
`DOSAGE AND ADMINISTRATION
`
`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: 4457960
`
`3
`
`

`

`
`DOSAGE FORMS AND STRENGTHS
`3
`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)].
`• Hypersensitivity 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 (5.10) 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 (14.3)], 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.
`
`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
`
`
`
`Reference ID: 4457960
`
`4
`
`

`

`
`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 m2. Use of GLYXAMBI is not recommended when eGFR is persistently less than 45
`
`
`
`Reference ID: 4457960
`
`5
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`

`

`
`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
`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)].
`
`
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`6
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`Reference ID: 4457960
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`

`

`
`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)]
`
`
`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-
`
`
`
`Reference ID: 4457960
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`7
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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 (%)
`
`34 (12.5)
`31 (11.4)
`Urinary tract infectiona
`16 (5.9)
`18 (6.6)
`Nasopharyngitis
`19 (7.0)
`19 (7.0)
`Upper respiratory tract infection
`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.
`
`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.
`
`
`
`
`Reference ID: 4457960
`
`8
`
`

`

`
`
`
`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
`GLYXAMBI
`GLYXAMBI
`Add-on to Metformin
`25 mg/5 mg
`10 mg/5 mg
`(52 weeks)
`(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
`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
`
`
`
`Reference ID: 4457960
`
`9
`
`

`

`• Severe and Disabling Arthralgia
`• Bullous Pemphigoid
`• Skin Reactions (e.g., rash, urticaria)
`• Mouth Ulceration, Stomatitis
`• Rhabdomyolysis
`
`
`
` 7
`
`DRUG INTERACTIONS
`
`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)].
`
`Positive Urine Glucose Test
`Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors
`as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use
`alternative methods to monitor glycemic control.
`
`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable
`in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic
`control.
`
`7.2 Drug Interactions with Linagliptin
`Inducers of P-glycoprotein or CYP3A4 Enzymes
`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. Therefore, use of alternative treatments is
`strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see
`Clinical Pharmacology (12.3)].
`
`7.3 Insulin or Insulin Secretagogues
`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 hypoglycemia [see Warnings and Precautions
`(5.7)].
`
` 8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Risk Summary
`Based on animal data showing adverse renal effects from empagliflozin, GLYXAMBI is not recommended
`during the second and third trimesters of pregnancy.
`
`The limited available data with GLYXAMBI, linagliptin, or empagliflozin in pregnant women are not sufficient
`to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and
`fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
`
`