`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`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. (5.3)
`Impairment in Renal Function: Monitor renal function during therapy.
`
`
`
`
`
`
`
`
`More frequent monitoring is recommended in patients with eGFR below
`60 mL/min/1.73 m2. (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)
`
`
`
`• Macrovascular Outcomes: There have been no clinical studies
`
`
`
`establishing conclusive evidence of macrovascular risk reduction with
`
`GLYXAMBI or any other antidiabetic drug. (5.11)
`
`
`------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions associated with GLYXAMBI (a
`
`
`
`
`
`•
`5% or greater incidence) were urinary tract infections, nasopharyngitis,
`
`
`
`and upper respiratory tract infections. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
`
`Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906
`
`
`TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`Pregnancy: There are no adequate and well-controlled studies in
`
`
`
`
`•
`pregnant women. Use during pregnancy only if the potential benefit
`
`justifies the potential risk to the fetus. (8.1)
`
`
`
`
`Nursing Mothers: Discontinue GLYXAMBI or discontinue nursing (8.3)
`
`
`
`
`
`
`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-------------------------
`
`
`
`
`
`
`Warnings and Precautions (5.3, 5.5)
`12/2015
`
`
`
`
`
`
`Warnings and Precautions (5.10)
`8/2015
`
`----------------------------INDICATIONS AND USAGE--------------------------
`
`
`
`GLYXAMBI is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and
`
`
`
`
`dipeptidyl peptidase-4 (DPP-4) inhibitor combination product 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. (1)
`
`Limitations of use:
`
`
`
`
`
`
`Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
`
`•
`
`(1.1)
`
`
`
`Has not been studied in patients with a history of pancreatitis (1.1)
`
`•
`----------------------DOSAGE AND ADMINISTRATION----------------------
`
`
`
`The recommended dose of GLYXAMBI is
`
`•
`
`
`
`
`10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning,
`
`
`with or without food (2.1)
`
`
`
`
`
`Dose may be increased to 25 mg empagliflozin/5 mg linagliptin once
`
`daily (2.1)
`
`
`
`Assess renal function before initiating GLYXAMBI. Do not initiate
`GLYXAMBI if eGFR is below 45 mL/min/1.73 m2 (2.2)
`
`
`
`
`
`
`Discontinue GLYXAMBI if eGFR falls persistently below
`45 mL/min/1.73 m2 (2.2)
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`Tablets:
`
`
`
`10 mg empagliflozin/5 mg linagliptin
`
`
`
`25 mg empagliflozin/5 mg linagliptin (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`
`
`
`Severe renal impairment, end-stage renal disease, or dialysis (4)
`
`•
`
`
`
`History of 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
`
`
`
`for signs and symptoms during therapy. (5.2)
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`Revised: 12/2015
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`5.10 Severe and Disabling Arthralgia
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`5.11 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`1
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Drug Interactions with Empagliflozin
`
`
`
`7.2 Drug Interactions with Linagliptin
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`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
`
`
`
`
`
`INDICATIONS AND USAGE
`
`1.1 Limitations of Use
`
`
`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 Hypotension
`
`
`5.3 Ketoacidosis
`
`
`5.4
`Impairment in Renal Function
`
`
`5.5 Urosepsis and Pyelonephritis
`
`
`5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`
`
`
`Secretagogues
`
`5.7 Genital Mycotic Infections
`
`
`
`5.8 Hypersensitivity Reactions
`
`
`5.9
`Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`
`
`
`
`
`
`
`Reference ID: 3856020
`
`
`
` 1
`
`
`
`
` 12.3 Pharmacokinetics
`
` 13 NONCLINICAL TOXICOLOGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
`
`
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
` *Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`
`
`
`
`Reference ID: 3856020
`
`
`
` 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` 1
` INDICATIONS AND USAGE
` GLYXAMBI tablets are 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 [see Clinical
`
` Studies (14)].
`
` 1.1 Limitations of Use
`
`
`
` GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
`
`
`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 persistently 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:
`
`
`
`• 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".
`
`
`
`
`
`Reference ID: 3856020
`
`
`
` 3
`
`
`
`
`
` • 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 Ketoacidos is
`
`
`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. 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.
`
`
`
`
`
`
`
`
`
`Reference ID: 3856020
`
`
`
` 4
`
`
`
`
`
`
`
`
`
`
` 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 Impairment in Renal Function
`
`
`Empagliflozin increases serum creatinine and decreases eGFR. The risk of impaired renal function with
`
`
`
`empagliflozin is increased in elderly patients and patients with moderate renal impairment. More frequent
`
`monitoring of renal function is recommended in these patients [see Use in Specific Populations (8.5, 8.6)].
`
`
`
`
`Renal function should be evaluated prior to initiating GLYXAMBI and periodically thereafter.
`
`
`
`
` 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.
`
`
`
`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.
`
`
`
`
`
`Reference ID: 3856020
`
`
`
` 5
`
`
`
`
` 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 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`GLYXAMBI or any other antidiabetic drug.
`
`
`
`
`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.
`
`
`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%).
`
`
`
`
`
`
`
`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
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`treated with placebo included: nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1%
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`and 1.4%).
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`Reference ID: 3856020
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` 6
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` Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were
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` hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and
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` myalgia.
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`In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while
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`being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with
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`comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported
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`following the last administered dose of linagliptin.
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`Hypoglycemia
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`Table 2 summarizes the reports of hypoglycemia with empagliflozin and linagliptin over a treatment period of
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`52 weeks.
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`Table 2 Incidence of Overalla and Severeb Hypoglycemic Adverse Reactions
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` GLYXAMBI
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` GLYXAMBI
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` Add-on to Metformin
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` 25 mg/5 mg
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` 10 mg/5 mg
` (52 weeks)
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` (n=137)
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` (n=136)
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` 3.6%
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` 2.2%
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` Overall (%)
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` Severe (%)
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` 0%
` 0%
` aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistance
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`bSevere hypoglycemic events: requiring assistance regardless of blood glucose
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` Laboratory Tests
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` Empagliflozin and Linagliptin
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` Changes in laboratory findings in patients treated with the combination of empagliflozin and linagliptin
` included increases in cholesterol and hematocrit compared to baseline.
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` Empagliflozin
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`Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein
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`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
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`Warnings and Precautions (5.9)]. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across
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`treatment groups.
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`Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in
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`empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%,
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`and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of
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`the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
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`Linagliptin
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`Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the
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`placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).
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`6.2 Postmarketing Experience
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`Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin.
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`Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible
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`to reliably estimate their frequency or establish a causal relationship to drug exposure.
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`• Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.1) and Warnings and
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`Precautions (5.1)]
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`• Ketoacidosis [see Warnings and Precautions (5.3)]
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`Reference ID: 3856020
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` • Urosepsis and pyelonephritis [see Warnings and Precautions (5.5)]
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` • Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see
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` Warnings and Precautions (5.8)]
` • Severe and disabling arthralgia [see Warnings and Precautions (5.10)]
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` • Rash
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` • Mouth ulceration, stomatitis
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`DRUG INTERACTIONS
`7
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`7.1 Drug Interactions with Empagliflozin
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`Diuretics
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`Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids,
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`which might enhance the potential for volume depletion [see Warnings and Precautions (5.2)].
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`Insulin or Insulin Secretagogues
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`Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia
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`[see Warnings and Precautions (5.6)].
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`Positive Urine Glucose Test
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`Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors
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`as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use
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`alternative methods to monitor glycemic control.
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`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
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`Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable
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`in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic
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`control.
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`7.2 Drug Interactions with Linagliptin
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`Inducers of P-glycoprotein or CYP3A4 Enzymes
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`Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when
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`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
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`Clinical Pharmacology (12.3)].
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`USE IN SPECIFIC POPULATIONS
`8
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`8.1 Pregnancy
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`Pregnancy Category C
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`GLYXAMBI
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`There are no adequate and well-controlled studies in pregnant women with GLYXAMBI or its individual
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`components. GLYXAMBI should be used during pregnancy only if the potential benefit justifies the potential
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`risk to the fetus.
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`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
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`and 353 times the clinical exposure. Maternal effects were limited to dose-related reduced body weight gain
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`and concomitant reduced food consumption in pregnant rats administered a combination of ≥300 mg/kg/day
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`Reference ID: 3856020
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` empagliflozin and 60 mg/kg/day linagliptin which is 99 and 227 times the clinical exposure. A pre- and post
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` natal development study was not conducted with the combined components of GLYXAMBI.
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`Empagliflozin
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`Based on results from animal studies, empagliflozin may affect renal development and maturation. In studies
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`conducted in rats, empagliflozin crosses the placenta and reaches fetal tissues. During pregnancy, consider
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`appropriate alternative therapies, especially during the second and third trimesters.
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`In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6
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`through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum
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`clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or
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`equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose).
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`Linagliptin
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`No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when
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`administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended
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`human dose, based on exposure.
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`Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
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`8.3 Nursing Mothers
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`No studies in lactating animals have been conducted with the combined components of GLYXAMBI.
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`Available animal data have shown excretion of empagliflozin and linagliptin in milk. It is not known whether
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`empagliflozin and linagliptin are excreted in human milk. Empagliflozin is secreted in the milk of lactating rats
`reaching levels up to 5 times higher than that in maternal plasma. Since human kidney maturation occurs in
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`utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the
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`developing human kidney. Because many drugs are excreted in human milk and because of the potential for
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`serious adverse reactions in nursing infants from empagliflozin, a decision should be made whether to
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`discontinue nursing or to discontinue GLYXAMBI, taking into account the importance of the drug to the
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`mother.
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`8.4 Pediatric Use
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`Safety and effectiveness of GLYXAMBI in pediatric patients under 18 years of age have not been established.
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`8.5 Geriatric Use
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`GLYXAMBI
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`Empagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years
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`and older.
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`Empagliflozin
`No empagliflozin dosage change is recommended based on age [see Dosage and Administration (2)]. A total of
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`2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of
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`age and older. Empagliflozin is expected to have diminished efficacy in elderly patients with renal impairment
`[see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in
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`patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and
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`empagliflozin 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and
`older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin
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`25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
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`Reference ID: 3856020
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` Linagliptin
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` There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of linagliptin; 1085
` (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in
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` 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years
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` and over. No overall differences in safety or effectiveness were observed between patients 65 years and over
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` and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical
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`studies of linagliptin have not identified differences in response between the elderly and younger patients,
`greater sensitivity of some older individuals cannot be ruled out.
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`8.6 Renal Impairment
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`Empagliflozin
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`The efficacy and safety of empagliflozin have not been established in patients with severe renal impairment,
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`with ESRD, or receiving dialysis. Empagliflozin is not expected to be effective in these patient populations
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`[see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2, 5.4)].
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` The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The
` risks of renal impairment [see Warnings and Precautions (5.4)], volume depletion adverse reactions and urinary
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` tract infection-related adverse reactions increased with worsening renal function.
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` 8.7 Hepatic Impairment
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` GLYXAMBI may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
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`10 OVERDOSAGE
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`In the event of an overdose with GLYXAMBI, contact the Poison Control Center. Employ the usual supportive
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`measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and
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`institute supportive treatment) as dictated by the patient’s clinical status. Re