`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`206073Orig1s021
`
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`GLYXAMBI
`
`Empagliflozin and Linagliptin
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`03/30/20
`
` GLYXAMBI is a combination of empagliflozin, a sodium-
`glucose cotransporter 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.
`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`206073Orig1s021
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`
`
`
`X
`X
`
`
`X
`
`
`
`
`
`X
`X
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`206073Orig1s021
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
` NDA 201280/S-020
`
` NDA 201281/S-024
`
`
` NDA 206073/S-021
`
`
` NDA 208026/S-012
`
`
`
`
`
`
`
`
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
` Boehringer Ingelheim Pharmaceuticals, Inc.
`
`
` Attention: Charles Mazzarella
` Director, Regulatory Affairs; and
`
` Madhuri Jerfy, M.S.
` Associate Director, Regulatory Affairs
`
`
` 900 Ridgebury Road, P.O. Box 368
`
` Ridgefield, CT 06877
`
`
` Dear Mr. Mazzarella and Ms. Jerfy:
`
` Please refer to your supplemental new drug applications (sNDAs) dated and received
`
`
`
`
`
`
` May 30, 2019 (NDA 201280) and June 6, 2019 (NDA 201281, NDA 206073, NDA
` 208026), and your amendments, submitted under section 505(b) and pursuant to
`
`
`
`
` section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Tradjenta
` (linagliptin) tablets, Jentadueto (linagliptin and metformin hydrochloride) tablets,
`
` Glyxambi (empagliflozin and linagliptin) tablets, and Jentadueto XR (linagliptin and
`
` metformin hydrochloride extended-release) tablets.
`
` These Prior Approval supplemental new drug applications provide for revisions to the
`
`
`
`
`
`
`
` prescribing information to include information based on Study 1218.74 entitled, A
`multicenter, international, randomized parallel group, double-blind trial to evaluate
`
`
`
` cardiovascular safety of linagliptin versus glimepiride in patients with T2DM at high
`
` cardiovascular risk. The CAROLINA trial.
`
` APPROVAL & LABELING
`
`We have completed our review of these applications, as amended. They are approved,
`
`
`
`
`
`
`effective on the date of this letter, for use as recommended in the enclosed agreed-
`
`
`upon labeling.
`
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`
`
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`
`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
`
`
`
`
`
`
`
`
`
`Reference ID: 4583067
`
`
`
`
`
`
`
`
` NDA 201280/S-020
`
` NDA 201281/S-024
`
` NDA 206073/S-021
`NDA 208026/S-012
`
`
` Page 2
`
`
` CONTENT OF LABELING
`
` As soon as possible, but no later than 14 days from the date of this letter, submit the
`
`
`
`
` content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`
`
`
`
` the FDA automated drug registration and listing system (eLIST), as described at
`
`
`
`
` FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`
`
`
`Prescribing Information and Medication Guide), with the addition of any labeling
`
`
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`
`reportable changes not included in the enclosed labeling.
`
`
`Information on submitting SPL files using eList may be found in the guidance for
`
`
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`
`
`
`
`
`changes for these NDAs, including CBE supplements for which FDA has not yet issued
`
`
`
`
`an action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`
`
`
`format, that includes the changes approved in this supplemental application, as well as
`
`annual reportable changes. To facilitate review of your submission(s), provide a
`
`
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`
`
`Word version. The marked-up copy should provide appropriate annotations, including
`
`
`
`supplement number(s) and annual report date(s).
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`
`
`new active ingredients (which includes new salts and new fixed combinations), new
`
`
`indications, new dosage forms, new dosing regimens, or new routes of administration
`
`
`are required to contain an assessment of the safety and effectiveness of the product for
`
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`
`or inapplicable.
`
`
`
`Because none of these criteria apply to your applications, you are exempt from this
`
`requirement.
`
`
`
`
`
`
` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`
` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`
`
`www.fda.gov
`
`
`
`
`
`Reference ID: 4583067
`
`
`
`
` NDA 201280/S-020
`
` NDA 201281/S-024
`
` NDA 206073/S-021
`NDA 208026/S-012
`
`
` Page 3
`
`
` PROMOTIONAL MATERIALS
`
` You may request advisory comments on proposed introductory advertising and
`
`
`
`
`
` promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter
` requesting advisory comments, (2) the proposed materials in draft or mock-up form with
`
` annotated references, and (3) the Prescribing Information to:
`
`
`
`
`
`
`
`OPDP Regulatory Project Manager
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD
`
`
`
`
`format. For more information about submitting promotional materials in eCTD format,
`
`
`
`see the draft guidance for industry Providing Regulatory Submissions in Electronic and
`
`Non-Electronic Format-Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.3
`
`
`
`
`You must submit final promotional materials and Prescribing Information, accompanied
`
`
`
`by a Form FDA 2253, at the time of initial dissemination or publication
`
`
`
`
`
`
`
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`
`
`
`
`
`Instructions for completing the form can be found at FDA.gov.5 For more information
`about submission of promotional materials to the Office of Prescription Drug Promotion
`
`
`(OPDP), see FDA.gov.6
`
`
`REPORTING REQUIREMENTS
`
`
` We remind you that you must comply with reporting requirements for an approved NDA
`
` (21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
` version of a guidance, check the FDA guidance web page at
`
` https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`
`
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
`
` 6 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
`
`
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`
`
`www.fda.gov
`
`
`
`Reference ID: 4583067
`
`
`
`
` NDA 201280/S-020
`
` NDA 201281/S-024
`
` NDA 206073/S-021
`NDA 208026/S-012
`
`
` Page 4
`
`
` If you have any questions, call Richard Whitehead, Regulatory Project Manager, at
`
` (301) 796-4945.
`
`
`
`
`
`
`
`
`
`Sincerely,
`
`
`
`{See appended electronic signature page}
`
`
`Patrick Archdeacon, M.D.
`
`
`
`Associate Director for Therapeutics (Acting)
`
`
`Division of Diabetes, Lipid Disorders, and Obesity
`Office of Cardiology, Hematology, Endocrinology, and
`
`Nephrology
`
`
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Medication Guides
`
`
`
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`
`
`www.fda.gov
`
`
`
`Reference ID: 4583067
`
`
`
`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`PATRICK ARCHDEACON
`03/30/2020 12:55:09 PM
`
`Reference ID: 4583067
`
`(
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`206073Orig1s021
`
`LABELING
`
`
`
`
`
`
`
`
` 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 (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
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`6.1 Clinical Trials Experience
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`6.2 Postmarketing Experience
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`7 DRUG INTERACTIONS
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`*Sections or subsections omitted from the full prescribing information are not
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`7.1 Drug Interactions with Empagliflozin
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`7.2 Drug Interactions with Linagliptin
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`Reference ID: 4583067
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`FULL PRESCRIBING INFORMATION
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`INDICATIONS AND USAGE
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`GLYXAMBI is a combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to
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`improve glycemic control in adults with type 2 diabetes mellitus.
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`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)].
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`Limitations of Use
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`GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis
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`[see Warnings and Precautions (5.4)].
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` GLYXAMBI has not been studied in patients with a history of pancreatitis. It is unknown whether patients with
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` a history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI
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` [see Warnings and Precautions (5.1)].
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`DOSAGE AND ADMINISTRATION
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`2.1 Recommended Dosage
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`The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning,
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`taken with or without food. In patients tolerating GLYXAMBI, the dose may be increased to 25 mg
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`empagliflozin/5 mg linagliptin once daily.
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`In patients with volume depletion, correcting this condition prior to initiation of GLYXAMBI is recommended
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`[see Warnings and Precautions (5.3), Use in Specific Populations (8.5) and Patient Counseling Information
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`(17)].
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`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
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`therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic
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`control can occur.
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`2.2 Patients with Renal Impairment
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`Assessment of renal function is recommended prior to initiation of GLYXAMBI and periodically thereafter.
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`GLYXAMBI should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
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`No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
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`GLYXAMBI should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and
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`Precautions (5.3, 5.5) and Use in Specific Populations (8.6)].
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`Reference ID: 4583067
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` DOSAGE FORMS AND STRENGTHS
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` GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following
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`• 10 mg empagliflozin/5 mg linagliptin tablets are pale yellow, arc triangular, flat-faced, bevel-edged, film-
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`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is
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`debossed with “10/5”.
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`• 25 mg empagliflozin/5 mg linagliptin tablets are pale pink, arc triangular, flat-faced, bevel-edged, film-
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`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is
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`debossed with “25/5”.
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`CONTRAINDICATIONS
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`GLYXAMBI is contraindicated in patients with:
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`• Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].
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`• Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI, reactions such as
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`anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred
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`[see Warnings and Precautions (5.10) and Adverse Reactions (6)].
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Pancreat itis
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`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
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` with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the
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` CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute
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` pancreatitis, including fatal pancreatitis, in patients treated with linagliptin.
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` Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly
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` 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.
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` 5.2 Heart Failure
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` An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular
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` outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2
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` diabetes mellitus and atherosclerotic cardiovascular disease.
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`Consider the risks and benefits of GLYXAMBI prior to initiating treatment in patients at risk for heart failure,
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`such as those with a prior history of heart failure and a history of renal impairment, and observe these patients
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`for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart
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`failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to
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`current standards of care and consider discontinuation of GLYXAMBI.
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`5.3 Hypotension
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`Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating
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`empagliflozin [see Adverse Reactions (6.1)] particularly in patients with renal impairment, the elderly, in
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`patients with low systolic blood pressure, and in patients on diuretics. Before initiating GLYXAMBI, assess for
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`volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension
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`Reference ID: 4583067
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` after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see
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` Use in Specific Populations (8.5)].
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`5.4 Ketoacidosis
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`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been
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`identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium
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`glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been
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`reported in patients taking empagliflozin. GLYXAMBI is not indicated for the treatment of patients with type 1
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`diabetes mellitus [see Indications and Usage (1)].
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`Patients treated with GLYXAMBI who present with signs and symptoms consistent with severe metabolic
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`acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis
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`associated with GLYXAMBI may be present even if blood glucose levels are less than 250 mg/dL. If
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`ketoacidosis is suspected, GLYXAMBI should be discontinued, patient should be evaluated, and prompt
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`treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate
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`replacement.
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`In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of
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`ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood
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`glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs
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`and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included
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`nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases,
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`factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake,
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`surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or
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`pancreatic surgery), and alcohol abuse were identified.
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`Before initiating GLYXAMBI, consider factors in the patient history that may predispose to ketoacidosis
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`including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.
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`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)].
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`Consider monitoring for ketoacidosis and temporarily discontinuing GLYXAMBI in other clinical situations
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`known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk
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`factors for ketoacidosis are resolved prior to restarting GLYXAMBI.
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`Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue GLYXAMBI
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`and seek medical attention immediately if signs and symptoms occur.
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`5.5 Acute Kidney Injury
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`Empagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.3)] and can cause
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`renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury,
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`some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin;
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`some reports involved patients younger than 65 years of age.
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`Before initiating GLYXAMBI, consider factors that may predispose patients to acute kidney injury including
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`hypovolemia, chronic renal impairment, heart failure and concomitant medications (diuretics, ACE inhibitors,
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`ARBs, NSAIDs). Consider temporarily discontinuing GLYXAMBI in any setting of reduced oral intake (such
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`as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor
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`Reference ID: 4583067
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` patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue GLYXAMBI
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` promptly and institute treatment.
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`Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more
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`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
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`below 60 mL/min/1.73 m2. Use of GLYXAMBI is not recommended when eGFR is persistently less than 45
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`mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and
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`Administration (2.2), Contraindications (4) and Use in Specific Populations (8.6)].
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`5.6 Urosepsis and Pyelonephritis
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`There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis
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`requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with
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`SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of
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`urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].
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`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
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`Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in
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`combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a higher rate of
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`hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or
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`insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
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`5.8 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
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`Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening
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`necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance
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`in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been
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`reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and
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`death.
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`Patients treated with GLYXAMBI presenting with pain or tenderness, erythema, or swelling in the genital or
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`perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start
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`treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue
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`GLYXAMBI, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic
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`control.
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`5.9 Genital Mycotic Infections
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`Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a
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`history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic
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`infections. Monitor and treat as appropriate.
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`5.10 Hypersensitivity Reactions
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`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin
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`(one of the components of GLYXAMBI). These reactions include anaphylaxis, angioedema, and exfoliative
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`skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of
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`treatment with linagliptin, with some reports occurring after the first dose.
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`Angioedema has also been reported with other dipeptidyl pepti