`
`
`
` 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)
`3/2020
`
`
`Warnings and Precautions
`
`
`
`
`
`Pancreatitis (5.1)
`
`
`
`
`Ketoacidosis (5.4)
`
`
`
`Increased Low-Density Lipoprotein Cholesterol
`
`
`
`
`
`
`(LDL-C) – Removed
`
`
`
`
`Bullous Pemphigoid (5.12)
`
`
`
`
`Macrovascular Outcomes – Removed
`
`
`
`7/2019
`
`
`1/2020
`
`
`
`3/2020
`
`
`7/2019
`
`
`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. (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 (4, 5.10)
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
`
`
`Pancreatitis: There have been reports of acute pancreatitis, including
`•
`
`
`
`
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`
`GLYXAMBI. (5.1)
`
`
`
`Heart Failure: Heart failure has been observed with two other members
`
`
`
`
`of the DPP-4 inhibitor class. Consider risks and benefits of GLYXAMBI
`
`
`in patients who have known risk factors for heart failure. Monitor for
`
`signs and symptoms. (5.2)
`
`
`
`•
`
`
`
`
`
`
`
`
`
`Reference ID: 4583067
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`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: 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: 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. (5.10)
`
`
`
`
`
`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 reports of bullous pemphigoid
`
`
`requiring hospitalization. Tell patients to report development of blisters
`
`
`
`or erosions. If bullous pemphigoid is suspected, discontinue
`
`GLYXAMBI. (5.12)
`
`------------------------------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: 3/2020
`
`
`
` 1
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`7.3
`Insulin or Insulin Secretagogues
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`8.1 Pregnancy
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`8.2 Lactation
`
`
`
`8.4 Pediatric Use
`
`
`
`2.1 Recommended Dosage
`
`
`
`8.5 Geriatric Use
`
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`8.6 Renal Impairment
`
`
`
`4 CONTRAINDICATIONS
`
`
`8.7 Hepatic Impairment
`
`
`
`10 OVERDOSAGE
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`11 DESCRIPTION
`
`
`5.1 Pancreatitis
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`5.2 Heart Failure
`
`
`
`12.1 Mechanism of Action
`
`
`
`5.3 Hypotension
`
`
`
`12.2 Pharmacodynamics
`
`
`
`5.4 Ketoacidosis
`
`
`
`12.3 Pharmacokinetics
`
`
`
`
`5.5 Acute Kidney Injury
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`
`
`14 CLINICAL STUDIES
`
`Secretagogues
`
`
`
`
`14.1 GLYXAMBI Glycemic Control Studies
`
`
`
`
`
`5.8 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`
`
`
`14.2 Empagliflozin Cardiovascular Outcome Study in Patients with
`
`
`
`
`5.9 Genital Mycotic Infections
`
`
`
`Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular
`
`
`
`5.10 Hypersensitivity Reactions
`
`
`Disease
`
`
`
`5.11 Severe and Disabling Arthralgia
`
`
`
`
`14.3 Linagliptin Cardiovascular Safety Trials
`
`
`
`5.12 Bullous Pemphigoid
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`6 ADVERSE REACTIONS
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`7.1 Drug Interactions with Empagliflozin
`
`
`
`
`7.2 Drug Interactions with Linagliptin
`
`
`
`
`
`
`
`
`
`Reference ID: 4583067
`
`
`
` 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)].
`
`
`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: 4583067
`
`
`
` 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”.
`
`
`
`
`CONTRAINDICATIONS
`4
`
`
`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, reactions such as
`
`
`anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred
`
`[see Warnings and Precautions (5.10) and Adverse Reactions (6)].
`
`
`
`
`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pancreat itis
`
`
`
`
`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: 4583067
`
`
`
` 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,
`
`
`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)].
`
`
`
`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.
`
`
`5.5 Acute Kidney Injury
`
`
`
`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 impairment, 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
`
`
`
`
`
`Reference ID: 4583067
`
`
`
` 5
`
`
`
`
`
`
`
`
` 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
`
`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 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.
`
`
`Reference ID: 4583067
`
`
`
` 6
`
`
`
`
`
`
`There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients
`
`
`treated with empaglifozin (one of the components of GLYXAMBI).
`
`
`
`
`If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor
`
`
`until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with a previous serious
`
`
`
`hypersensitivity reaction to linagliptin or empagliflozin [see Contraindications (4)].
`
`
`
`
`5.11 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.
`
`
`
`5.12 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.
`
`
`ADVERSE REACTIONS
`6
`
`
`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 [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)]
`
`
`
`
`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.11)]
`
`
`
`
`• Bullous Pemphigoid [see Warnings and Precautions (5.12)]
`
`
`
`
`
`
`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.
`
`
`
`
`
`Reference ID: 4583067
`
`
`
` 7
`
`
`
`
`
`
`
`
` 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
`
`
`
` GLYXAMBI
`
` GLYXAMBI
`
`
` 25 mg/5 mg
` 10 mg/5 mg
`
`
` n=273
`
` n=272
`
` n (%)
`
` n (%)
`
`
` Urinary tract infectiona
`
` 31 (11.4)
`
` 34 (12.5)
`
` Nasopharyngitis
` 18 (6.6)
`
` 16 (5.9)
`
` 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
`
`
`
`
`
`
`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%).
`
`
`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: 4583067
`
`
`
` 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. 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.
`
`
`
`
`
`
`
`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 [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4583067
`
`
`
` 9
`
`
`
`
` 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 establis