CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`206073Orig1s017
`
`GLYXAMBI
`
`Generic Name: Empagliflozin and Linagliptin
`
`
`Trade Name:
`
`
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`07/03/2019
`
` 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. 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)
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`206073Orig1s017
`
`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
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`206073Orig1s017
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
` NDA 201280/S-018
`
` NDA 201281/S-022
`
` NDA 206073/S-017
`
` NDA 208026/S-008
`
`
`
`
` SUPPLEMENT APPROVAL
`
` FULFILLMENT OF POSTMARKETING
`
` REQUIREMENT
`
`
`
`
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`
`
`Attention: Joerg Schnitzler, Ph.D. and Madhuri Jerfy, M.S.
`
`
`Senior Associate Director and Associate Director, Regulatory Affairs
`
`
`
`900 Ridgebury Road, P.O. Box 368
`
`
`Ridgefield, CT 06877
`
`
`
`
`
`Dear Dr. Schnitzler and Ms. Jerfy:
`
`
`
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received
`
`
`
`
`September 5, 2018, for NDA 201280 and September 12, 2018, for NDA 201281, NDA
`
`
`
`
`206073, and 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 sNDAs provide for changes to the Prescribing Information and
`
`
`
`Medication Guides based on results of study 1218.22 entitled, “A Multicenter,
`
`
`International, Randomized, Parallel Group, Double-blind, Placebo-Controlled
`
`Cardiovascular Safety and Renal Microvascular Outcome Study with Linagliptin, 5 mg
`
`
`
`
`Once Daily in Patients with Type 2 Diabetes Mellitus at High Vascular Risk,”
`
`
`
`
`(CARMELINA). The CARMELINA trial was conducted to fulfill PMR 1766-4 for NDA
`
`201280.
`
`
`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: 4457960
`
`

`

`
` NDA 201280/S-018
`
` NDA 201281/S-022
`
` NDA 206073/S-017
`
` NDA 208026/S-008
`
` 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 this NDA, 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 application, 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: 4457960
`
`

`

`
` NDA 201280/S-018
`
` NDA 201281/S-022
`
` NDA 206073/S-017
`
` NDA 208026/S-008
`
` Page 3
`
`
`FULFILLMENT OF POSTMARKETING REQUIREMENT
`
`
`The supplemental application for NDA 201280 contained the final report for the
`
`
`
`following postmarketing requirement listed in the May 2, 2011, approval letter for NDA
`
`
`
`
`
`
`201280.
`
`
`
`
`
`
`
`
`
`
` 1766-4 A randomized, double-blind, placebo-controlled trial evaluating the effect
`
` of Tradjenta (linagliptin) tablets on the incidence of major adverse
`
`
` cardiovascular events in patients with type 2 diabetes mellitus.
`
`
`
`
`
`
`We have reviewed your submission and conclude that the above requirement was
`
`
`fulfilled.
`
`
`
`We remind you that there is a postmarketing requirement listed in the December 22,
`
`
`
`
`
`2017, postapproval postmarketing requirement letter that is still open for NDA 201280.
`
`
`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
`
`
`
` 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.
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`
`Reference ID: 4457960
`
`

`

`
` NDA 201280/S-018
`
` NDA 201281/S-022
`
` NDA 206073/S-017
`
` NDA 208026/S-008
`
` Page 4
`
`
`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).
`
`
` If you have any questions, call Richard Whitehead, M.S., Regulatory Project Manager,
`
` at (301) 796-4945.
`
`
`
`
`
`
`
`
`
`
`
`
` Sincerely,
`
` {See appended electronic signature page}
`
` Lisa B. Yanoff, M.D.
`
` Director (Acting)
` Division of Metabolism and Endocrinology Products
`
` Office of Drug Evaluation II
` Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ENCLOSURES:
`
`
` • Content of Labeling (Prescribing Information and Medication Guides) for
`
`
`
`
`
`
` Tradjenta, Jentadueto, Glyxambi, and Jentadueto XR
`
`
`
`
`
`
`
`
`
`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: 4457960
`
`

`

`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/
`------------------------------------------------------------
`
`LISA B YANOFF
`07/03/2019 03:08:51 PM
`
`Reference ID: 4457960
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`206073Orig1s017
`
`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--------------------------
`Warnings and Precautions
` 7/2019
`
`
`
` Pancreatitis (5.1)
`
` Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) (5.8) 10/2018
` Bullous Pemphigoid (5.13)
`
`
`
` 7/2019
` Macrovascular Outcomes – Removed
`
`
` 7/2019
`
`----------------------------INDICATIONS AND USAGE---------------------------
`GLYXAMBI is a combination of empagliflozin, a sodium-glucose co-
`transporter 2 (SGLT2) inhibitor and linagliptin, a dipeptidyl peptidase-4
`(DPP-4) inhibitor, indicated as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`
`Empagliflozin is indicated to reduce the risk of cardiovascular death in adults
`with type 2 diabetes mellitus and established cardiovascular disease.
`However, the effectiveness of GLYXAMBI on reducing the risk of
`cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular
`disease has not been established (1)
`
`Limitations of Use
`•
`Not recommended for patients with type 1 diabetes or for the treatment
`of diabetic ketoacidosis (1)
`Has not been studied in patients with a history of pancreatitis (1)
`
`•
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`•
`The recommended dose of GLYXAMBI is
`10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning,
`with or without food (2.1)
`Dose may be increased to 25 mg empagliflozin/5 mg linagliptin once
`daily (2.1)
`Assess renal function before initiating GLYXAMBI. Do not initiate
`GLYXAMBI if eGFR is below 45 mL/min/1.73 m2 (2.2)
`Discontinue GLYXAMBI if eGFR falls persistently below 45
`mL/min/1.73 m2 (2.2)
`
`•
`
`•
`
`•
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets:
`10 mg empagliflozin/5 mg linagliptin
`25 mg empagliflozin/5 mg linagliptin (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`•
`Severe renal impairment, end-stage renal disease, or dialysis (4)
`•
`Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in
`GLYXAMBI such as anaphylaxis, angioedema, exfoliative skin
`conditions, urticaria, or bronchial hyperreactivity (4)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`•
`Pancreatitis There have been reports of acute pancreatitis, including
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`GLYXAMBI. (5.1)
`Heart Failure Heart failure has been observed with two other members
`of the DPP-4 inhibitor class. Consider risks and benefits of GLYXAMBI
`
`•
`
`
`
`
`
`
`
`Reference ID: 4457960
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`•
`
`•
`
`in patients who have known risk factors for heart failure. Monitor for
`signs and symptoms. (5.2)
`Hypotension Before initiating GLYXAMBI assess and correct volume
`status in patients with renal impairment, the elderly, in patients
`with low systolic blood pressure, and in patients on diuretics. Monitor
`for signs and symptoms during therapy. (5.3)
`Ketoacidosis Assess patients who present with signs and symptoms of
`metabolic acidosis for ketoacidosis, regardless of blood glucose level. If
`suspected, discontinue GLYXAMBI, evaluate and treat promptly.
`Before initiating GLYXAMBI, consider risk factors for ketoacidosis.
`Patients on GLYXAMBI may require monitoring and temporary
`discontinuation of therapy in clinical situations known to predispose to
`ketoacidosis. (5.4)
`Acute Kidney Injury and Impairment in Renal Function Consider
`temporarily discontinuing in settings of reduced oral intake or fluid
`losses. If acute kidney injury occurs, discontinue and promptly treat.
`Monitor renal function during therapy. (5.5)
`Urosepsis and Pyelonephritis Evaluate patients for signs and symptoms
`of urinary tract infections and treat promptly, if indicated (5.6)
`Hypoglycemia Consider lowering the dose of insulin secretagogue or
`insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI.
`(5.7)
`Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Serious,
`life-threatening cases have occurred in both females and males. Assess
`patients presenting with pain or tenderness, erythema, or swelling in the
`genital or perineal area, along with fever or malaise. If suspected,
`institute prompt treatment. (5.8)
`Genital Mycotic Infections Monitor and treat as appropriate (5.9)
`Hypersensitivity Reactions Discontinue GLYXAMBI, treat promptly,
`and monitor until signs and symptoms resolve. (5.10)
`Increased LDL-C Monitor and treat as appropriate (5.11)
`Arthralgia Severe and disabling arthralgia has been reported in patients
`taking DPP-4 inhibitors. Consider as a possible cause for severe joint
`pain and discontinue drug if appropriate. (5.12)
`Bullous Pemphigoid There have been reports of bullous pemphigoid
`requiring hospitalization. Tell patients to report development of blisters
`or erosions. If bullous pemphigoid is suspected, discontinue
`GLYXAMBI. (5.13)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`•
`The most common adverse reactions associated with GLYXAMBI (a
`5% or greater incidence) were urinary tract infections, nasopharyngitis,
`and upper respiratory tract infections (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
`Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906
`TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`•
`Pregnancy Advise females of the potential risk to a fetus especially
`during the second and third trimesters (8.1)
`Lactation GLYXAMBI is not recommended when breastfeeding (8 2)
`Pediatric Patients: Safety and effectiveness of GLYXAMBI in pediatric
`patients have not been established (8.4)
`Geriatric Patients Higher incidence of adverse reactions related to
`volume depletion and reduced renal function (5.3, 5.5, 8.5)
`Renal Impairment Higher incidence of adverse reactions related to
`reduced renal function (2.2, 5.5, 8.6)
`
`•
`•
`
`•
`
`•
`
`Revised: 7/2019
`
`1
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
`
`

`

`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`7.2 Drug Interactions with Linagliptin
`7.3
`Insulin or Insulin Secretagogues
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 GLYXAMBI Glycemic Control Studies
`14.2 Empagliflozin Cardiovascular Outcome Study in Patients with
`Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular
`Disease
`14.3 Linagliptin Cardiovascular Safety Trial
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
` INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Patients with Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Heart Failure
`5.3 Hypotension
`5.4 Ketoacidosis
`5.5 Acute Kidney Injury and Impairment in Renal Function
`5.6 Urosepsis and Pyelonephritis
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues
`5.8 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`5.9 Genital Mycotic Infections
`5.10 Hypersensitivity Reactions
`5.11 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`5.12 Severe and Disabling Arthralgia
`5.13 Bullous Pemphigoid
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Drug Interactions with Empagliflozin
`
` 1
`
`
`
`
`
`
`
`
`Reference ID: 4457960
`
`2
`
`

`

`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`GLYXAMBI is a combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus.
`
`Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and
`established cardiovascular disease [see Clinical Studies (14.2)]. However, the effectiveness of GLYXAMBI on
`reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has
`not been established.
`
`Limitations of Use
`GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis
`[see Warnings and Precautions (5.4)].
`
`GLYXAMBI has not been studied in patients with a history of pancreatitis. It is unknown whether patients with
`a history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI
`[see Warnings and Precautions (5.1)].
`
` 2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning,
`taken with or without food. In patients tolerating GLYXAMBI, the dose may be increased to 25 mg
`empagliflozin/5 mg linagliptin once daily.
`
`In patients with volume depletion, correcting this condition prior to initiation of GLYXAMBI is recommended
`[see Warnings and Precautions (5.3), Use in Specific Populations (8.5) and Patient Counseling Information
`(17)].
`
`No studies have been performed specifically examining the safety and efficacy of GLYXAMBI in patients
`previously treated with other oral antihyperglycemic agents and switched to GLYXAMBI. Any change in
`therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic
`control can occur.
`
`2.2 Patients with Renal Impairment
`Assessment of renal function is recommended prior to initiation of GLYXAMBI and periodically thereafter.
`
`GLYXAMBI should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
`
`No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
`
`GLYXAMBI should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and
`Precautions (5.3, 5.5) and Use in Specific Populations (8.6)].
`
`
`
`
`Reference ID: 4457960
`
`3
`
`

`

`
`DOSAGE FORMS AND STRENGTHS
`3
`GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following
`dosage forms and strengths:
`
` •
`
` 10 mg empagliflozin/5 mg linagliptin tablets are pale yellow, arc triangular, flat-faced, bevel-edged, film-
`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is
`debossed with “10/5”.
`
` •
`
` 25 mg empagliflozin/5 mg linagliptin tablets are pale pink, arc triangular, flat-faced, bevel-edged, film-
`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is
`debossed with “25/5”.
`
` 4
`
`CONTRAINDICATIONS
`
`GLYXAMBI is contraindicated in patients with:
`• Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].
`• Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI such as anaphylaxis,
`angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity [see Warnings and
`Precautions (5.10) and Adverse Reactions (6)].
`
` 5
`
` WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the
`CARMELINA trial [see Clinical Studies (14.3)], acute pancreatitis was reported in 9 (0.3%) patients treated
`with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the
`CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute
`pancreatitis, including fatal pancreatitis, in patients treated with linagliptin.
`
`Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly
`discontinue GLYXAMBI and initiate appropriate management. It is unknown whether patients with a history
`of pancreatitis are at increased risk for the development of pancreatitis while using GLYXAMBI.
`
`5.2 Heart Failure
`An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular
`outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2
`diabetes mellitus and atherosclerotic cardiovascular disease.
`
`Consider the risks and benefits of GLYXAMBI prior to initiating treatment in patients at risk for heart failure,
`such as those with a prior history of heart failure and a history of renal impairment, and observe these patients
`for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart
`failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to
`current standards of care and consider discontinuation of GLYXAMBI.
`
`5.3 Hypotension
`Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating
`empagliflozin [see Adverse Reactions (6.1)] particularly in patients with renal impairment, the elderly, in
`patients with low systolic blood pressure, and in patients on diuretics. Before initiating GLYXAMBI, assess for
`volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension
`
`
`
`Reference ID: 4457960
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`
`after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see
`Use in Specific Populations (8.5)].
`
`5.4 Ketoacidosis
`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been
`identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium
`glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been
`reported in patients taking empagliflozin. GLYXAMBI is not indicated for the treatment of patients with type 1
`diabetes mellitus [see Indications and Usage (1)].
`
`Patients treated with GLYXAMBI who present with signs and symptoms consistent with severe metabolic
`acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis
`associated with GLYXAMBI may be present even if blood glucose levels are less than 250 mg/dL. If
`ketoacidosis is suspected, GLYXAMBI should be discontinued, patient should be evaluated, and prompt
`treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate
`replacement.
`
`In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of
`ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood
`glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs
`and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included
`nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases,
`factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake
`due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of
`pancreatitis or pancreatic surgery), and alcohol abuse were identified.
`
`Before initiating GLYXAMBI, consider factors in the patient history that may predispose to ketoacidosis
`including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated
`with GLYXAMBI consider monitoring for ketoacidosis and temporarily discontinuing GLYXAMBI in clinical
`situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
`
`5.5 Acute Kidney Injury and Impairment in Renal Function
`Empagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.3)] and can cause
`renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury,
`some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin;
`some reports involved patients younger than 65 years of age.
`
`Before initiating GLYXAMBI, consider factors that may predispose patients to acute kidney injury including
`hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE
`inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing GLYXAMBI in any setting of reduced oral
`intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat
`exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs,
`discontinue GLYXAMBI promptly and institute treatment.
`
`Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more
`susceptible to these changes. Renal function abnormalities can occur after initiating GLYXAMBI [see Adverse
`Reactions (6.1)]. Renal function should be evaluated prior to initiation of GLYXAMBI and monitored
`periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR
`below 60 mL/min/1.73 m2. Use of GLYXAMBI is not recommended when eGFR is persistently less than 45
`
`
`
`Reference ID: 4457960
`
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`mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and
`Administration (2.2), Contraindications (4) and Use in Specific Populations (8.6)].
`
`5.6 Urosepsis and Pyelonephritis
`There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis
`requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with
`SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of
`urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].
`
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in
`combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a higher rate of
`hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or
`insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
`
`5.8 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening
`necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance
`in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been
`reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and
`death.
`
`Patients treated with GLYXAMBI presenting with pain or tenderness, erythema, or swelling in the genital or
`perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start
`treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue
`GLYXAMBI, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic
`control.
`
`5.9 Genital Mycotic Infections
`Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a
`history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic
`infections. Monitor and treat as appropriate.
`
`5.10 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin
`(one of the components of GLYXAMBI). These reactions include anaphylaxis, angioedema, and exfoliative
`skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with
`linagliptin, with some reports occurring after the first dose.
`
`Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a
`patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients
`will be predisposed to angioedema with GLYXAMBI.
`
`There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients
`treated with empaglifozin (one of the components of GLYXAMBI).
`
`If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor
`until signs and symptoms resolve. GL