`
`
`
`
`
`
`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. (5.3)
`
`
`
`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 (5.4)
`Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms
`
`
`
`
`of urinary tract infections and treat promptly, if indicated (5.5)
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or
`
`
`
`
`
`insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI.
`
`(5.6)
`
`Genital Mycotic Infections: Monitor and treat as appropriate (5.7)
`
`
`
`Hypersensitivity: There have been postmarketing reports of serious
`
`
`
`
`hypersensitivity reactions in patients treated with linagliptin (one of the
`
`
`
`components of GLYXAMBI) including anaphylaxis, angioedema, and
`
`
`
`exfoliative skin conditions. In such cases, promptly discontinue
`GLYXAMBI, assess for other potential causes, institute appropriate
`
`
`
`monitoring and treatment, and initiate alternative treatment for diabetes.
`
`(5.8)
`Increased LDL-C: Monitor and treat as appropriate (5.9)
`
`
`
`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. (5.10)
`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. (5.11)
`
`
`
`• Macrovascular Outcomes: There have been no clinical studies
`
`
`
`establishing conclusive evidence of macrovascular risk reduction with
`
`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 (5.2, 5.4, 8.5)
`
`
`Renal Impairment: Higher incidence of adverse reactions related to
`
`
`
`reduced renal function (2.2, 5.4, 8.6)
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
` 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--------------------------
`
`
`
`
`
`
`Indications and Usage
`12/2016
`
`
`
`
`
`
`
`Warnings and Precautions (5)
`12/2016
`
`----------------------------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 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 hypersensitivity reaction to linagliptin, such as anaphylaxis,
`
`•
`
`
`
`angioedema, exfoliative skin conditions, urticaria, or bronchial
`
`hyperreactivity (4)
`
`
`
`
`History of serious hypersensitivity reaction to empagliflozin (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)
`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
`Revised: 12/2016
`
`
`
`
`
`
`
`
`for signs and symptoms during therapy. (5.2)
`_______________________________________________________________________________________________________________________________________
`5.7 Genital Mycotic Infections
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`5.8 Hypersensitivity Reactions
`
`
`
`5.9
`Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`INDICATIONS AND USAGE
`1
`
`
`
`
`
`
`
`5.10 Severe and Disabling Arthralgia
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
`5.11 Bullous Pemphigoid
`
`
`2.1 Recommended Dosage
`
`
`5.12 Macrovascular Outcomes
`
`
`2.2 Patients with Renal Impairment
`
`
`
`6 ADVERSE REACTIONS
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`6.1 Clinical Trials Experience
`4 CONTRAINDICATIONS
`
`
`
`
`6.2 Postmarketing Experience
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`7 DRUG INTERACTIONS
`
`5.1 Pancreatitis
`
`
`
`7.1 Drug Interactions with Empagliflozin
`
`
`
`5.2 Hypotension
`
`
`7.2 Drug Interactions with Linagliptin
`
`
`
`5.3 Ketoacidosis
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`
`
`
`8.1 Pregnancy
`
`
`5.5 Urosepsis and Pyelonephritis
`
`
`8.2 Lactation
`
`
`5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`
`
`8.4 Pediatric Use
`
`
`Secretagogues
`
`
`
`
`Reference ID: 4033068
`
`
`
` 1
`
`
`
`
`
` 8.5 Geriatric Use
`
`
` 8.6 Renal Impairment
`
` 8.7 Hepatic Impairment
` OVERDOSAGE
`
`10
`
`
` DESCRIPTION
`11
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13
`
`
`
`
`
`
`
`
`
`
`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
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`16
`
`17
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`Reference ID: 4033068
`
`
`
` 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 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 (5.3)].
`
`
`
`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 (5.2), 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 less than 45 mL/min/1.73 m2 [see Warnings and Precautions
`
`
`
`
`
`(5.2, 5.4), and Use in Specific Populations (8.6)].
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following
`
`
`
`dosage forms and strengths:
`
`
`
`
`
`
`
`
`
`
` 3
`
`Reference ID: 4033068
`
`
`
`
` • 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)].
`
`
`
`
`
`
`
`• A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin
`
`conditions, urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.8) and Adverse
`
`
`Reactions (6)].
`
`
`
`
`
`
`• History of serious hypersensitivity reaction to empagliflozin.
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pancreatitis
`
`
`There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking
`
`
`
`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 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)].
`
`
`
`5.3 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
`
`
`
`
`
`
`Reference ID: 4033068
`
`
`
` 4
`
`
`
`
`
`
`
`
` 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).
`
`
`
`5.4 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,
`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), Use in Specific Populations (8.6)].
`
`
`5.5 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)].
`
`
`5.6 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.
`
`
`5.7 Genital Mycotic Infections
`
`
`Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a
`
`
`
`
`history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital
`
`
`
`
`
`infections. Monitor and treat as appropriate.
`
`
`
`
`
`
`Reference ID: 4033068
`
`
`
` 5
`
`
`
`
`
`
`
`
` 5.8 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. If a serious hypersensitivity reaction is suspected,
`
`
`
` discontinue GLYXAMBI, assess for other potential causes for the event, and institute alternative treatment for
`
`
`
` diabetes.
`
`
`
`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.
`
`
`
`5.9 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.
`
`
`
`
`5.10 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.
`
`
`
`5.11 Bullous Pemphigoid
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor
`
`
`use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and
`discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while
`
`
`receiving GLYXAMBI. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued and referral
`
`to a dermatologist should be considered for diagnosis and appropriate treatment.
`
`
`5.12 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`GLYXAMBI.
`
`
`ADVERSE REACTIONS
`6
`
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`
`
`
`
`
`reflect the rates observed in practice.
`
`
`Empagliflozin and Linagliptin
`
`The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose
`
`
`
`5 mg) has been evaluated in a total of 1363 patients with type 2 diabetes treated for up to 52 weeks in active-
`controlled clinical trials. The most common adverse reactions with concomitant administration of
`
`
`empagliflozin and linagliptin based on a pooled analyses of these studies are shown in Table 1.
`
`
`
`
`
`Reference ID: 4033068
`
`
`
` 6
`
`
`
`
`
`
` 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.
`
`
`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.
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4033068
`
`
`
` 7
`
`
`
`
`
`
`
`
`
`
` 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 (5.9)]. 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
`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).
`
`
`
`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 (1.1) and Warnings and
`
`
`
`Precautions (5.1)]
`
`• Ketoacidosis [see Warnings and Precautions (5.3)]
`
`
`
`
`• Urosepsis and pyelonephritis [see Warnings and Precautions (5.5)]
`
`
`
`
`
`• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see
`
`
`Warnings and Precautions (5.8)]
`
`• Severe and disabling arthralgia [see Warnings and Precautions (5.10)]
`
`
`
`
`
`• Bullous pemphigoid [see Warnings and Precautions (5.11)]
`
`
`
`
`• Rash
`
`
`• 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 (5.2)].
`
`
`
`
`Insulin or Insulin Secretagogues
`
`Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia
`
`
`[see Warnings and Precautions (5.6)].
`
`
`
`
`
`
`Reference ID: 4033068
`
`
`
` 8
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`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).
`
`
`
`
`
`In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a
`
`period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses
`
`
`approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were
`
`reversible. No adverse developmental effects were observed when the combination of linagliptin and
`
`
`
`empagliflozin was administered to pregnant rats during the period of organogenesis at exposures approximately
`253 and 353 times the clinical exposure (see Data).
`
`
`
`
`The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a
`
`
`
`HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated
`
`background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the
`
`
`
`estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4%
`
`and15-20%, respectively.
`
`
`Clinical Considerations
`Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the
`
`maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and
`
`
`delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and
`
`
`
`
`macrosomia related morbidity.
`
`
`
`
`
`Reference ID: 4033068
`
`
`
` 9
`
`
`
`
`
`
`
`
` Data
`
` Animal Data
`
`The combined components administered during the period of organogenesis were not teratogenic in rats up to
`and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253
`
`
`and 353 times the clinical exposure. A pre- and post-natal development study was not conducted with the
`
`
`combined components of GLYXAMBI.
`
`
`
` Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at
`
`
` doses of 1, 10, 30 and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at
`
`
`
` 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based