`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`200678Orig1s000
`
`KOMBIGLYZE XR
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Saxagliptin and Metformin HCl extended-release
`
`Bristol-Myers Squibb
`
`11/05/2010
`
` An adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when
`treatment with both Saxagliptin and Metformin is
`appropriate
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`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)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`
`
`X
`X
`
`X
`X
`X
`X
`X
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 200678
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Bristol-Myers Squibb Company
`Attention: Pamela J. Smith, M.D.
`Group Director, Global Regulatory Strategy
`P.O. Box 4000
`Princeton, NJ 08543-4000
`
`
`Dear Dr. Smith:
`
`Please refer to your New Drug Application (NDA) dated December 29, 2009, received
`December 29, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for Kombiglyze XR (saxagliptin/metformin hydrochloride extended-release)
`tablets, 5 mg saxagliptin/500 mg metformin hydrochloride extended-release, 5 mg
`saxagliptin/1000 mg metformin hydrochloride extended-release, and 2.5 mg saxagliptin/1000 mg
`metformin hydrochloride extended-release.
`
`We acknowledge receipt of your amendments dated January 12, February 5, March 10 and 23,
`April 23, 26, 28, and 29, May 25, 27, and 28, June 16, July 20 and 23, August 3 and 13 (2),
`September 1, 21, 22, 24 (2), 28, 29 (2), and 30, October 6, 7, 8, 12, 19, 22, 27, and 28, and
`November 1, 2010.
`
`This new drug application provides for the use of Kombilyze XR (saxagliptin/metformin
`hydrochloride extended-release) tablets as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and
`metformin is appropriate.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`Sufficient stability data have been submitted to support a 21-month expiration dating period for
`the bottle presentations and a 15-month expiration dating period for the blister presentations.
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`
`
`
`Reference ID: 2860284
`
`

`

`
`
`
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert and the patient package insert).
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on October 22, 2010, as soon as they are available, but no more than
`30 days after they are printed. Please submit these labels electronically according to the
`guidance for industry titled “Providing Regulatory Submissions in Electronic Format – Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`(June 2008).” Alternatively, you may submit 12 paper copies, with 6 of the copies individually
`mounted on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “Final Printed Carton and Container Labels for approved NDA 200678.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, 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(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for ages 0 to 9 years (inclusive) because the
`necessary studies are impossible or highly impracticable (there are too few children in this age range
`with type 2 diabetes mellitus to study).
`
`We are deferring submission of your pediatric study for ages 10 to 16 years for this application
`because this product is ready for approval for use in adults and the pediatric studies have not
`been completed.
`
`
` NDA 200678
` Page 2
`
`
`
`
`Reference ID: 2860284
`
`

`

` NDA 200678
` Page 3
`
`
`
`
`
`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must
`be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the Federal Food,
`Drug, and Cosmetic Act. These required studies are listed below.
`
`PMR 1703-1: A clinical pharmacology study in pediatric patients with type 2 diabetes
`comparing the pharmacokinetics of Kombiglyze XR to co-administered saxagliptin and
`metformin immediate-release tablets. As part of this study, you must evaluate whether pediatric
`patients can safely swallow the large Kombiglyze XR tablets.
`
`
`Final Protocol Submission: by October 31, 2011
`Trial Completion:
`
`by January 31, 2013
`Final Report Submission:
`by December 2013
`
`
`PMR 1703-2: A 52-week, randomized, double-blind, placebo-controlled trial to evaluate the
`efficacy and safety of saxagliptin vs. placebo, both as add-on therapy to metformin in pediatric
`patients with inadequate glycemic control on metformin alone. Approximately one-half of the
`patients must be on metformin extended-release therapy at the time of randomization to add-on
`saxagliptin vs. add-on placebo. As part of this study, you must evaluate whether pediatric
`patients can safely swallow the large metformin extended-release tablets.
`
`
`Final Protocol Submission: by June 30, 2011
`Trial Completion:
`
`by April 30, 2015
`Final Report Submission:
`by December 31, 2015
`
`
`Submit final study reports to this NDA. For administrative purposes, all submissions related to
`these required pediatric postmarketing studies must be clearly designated “Required Pediatric
`Assessment(s)”.
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`
`
`Reference ID: 2860284
`
`

`

`NDA 200678
`Page 4
`
`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA to the following
`address:
`
`
`MedWatch Program
`Office of Special Health Issues
`Food and Drug Administration
`10903 New Hampshire Ave
`Building 32, Mail Stop 5353
`Silver Spring, MD 20993
`
`
`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 Raymond Chiang, Consumer Safety Officer, at (301) 796-1940.
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Mary H. Parks, M.D.
`Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ENCLOSURES:
`Package Insert
`Patient Package Insert
`Container Label – 2.5 mg/1000mg, 6 tablet blister card (sample)
`Container Label – 2.5mg/1000mg, 60 tablet bottle
`Container Label – 2.5 mg/1000mg, 500 tablet bottle
`Container Label – 5mg/500mg, 7 tablet blister card (sample)
`Container Label – 5mg/500mg, 30 tablet bottle
`Container Label – 5 mg/1000mg, 7 tablet blister card (sample)
`
`
`Reference ID: 2860284
`
`

`

`NDA 200678
`Page 5
`
`
`Container Label – 5 mg/ 1000mg, 30 tablet bottle
`Container Label – 5mg/1000mg, 90 tablet bottle
`Container Label – 5 mg/1000mg, 500 tablet bottle
`Carton Label - 2.5 mg/1000mg, 6 tablets (sample)
`Carton Label – 5mg/500mg, 7 tablets (sample)
`Carton Label – 5mg/1000mg, 7 tablets (sample)
`
`
`
`
`Reference ID: 2860284
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`11/05/2010
`
`Reference ID: 2860284
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`LABELING
`
`
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`KOMBIGLYZE XR safely and effectively. See
`full prescribing
`information for KOMBIGLYZE XR.
`KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release)
`tablets
`Initial U.S. Approval: 2010
`
`
`WARNING: LACTIC ACIDOSIS
`See full prescribing information for complete boxed warning.
`Lactic acidosis can occur due to metformin accumulation. The
`risk increases with conditions such as sepsis, dehydration, excess
`alcohol intake, hepatic impairment, renal impairment, and acute
`congestive heart failure. (5.1)
`Symptoms
`include malaise, myalgias, respiratory distress,
`increasing somnolence, and nonspecific abdominal distress.
`Laboratory abnormalities include low pH, increased anion gap,
`and elevated blood lactate. (5.1)
`If acidosis is suspected, discontinue KOMBIGLYZE XR and
`hospitalize the patient immediately. (5.1)
`
`•
`
`•
`
`•
`
`•
`
`---------------------------INDICATIONS AND USAGE----------------------------
`KOMBIGLYZE XR is a dipeptidyl peptidase-4 inhibitor and biguanide
`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 saxagliptin and metformin is appropriate. (1, 14)
`Important limitations of use:
`•
`Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.1)
`•
`Has not been studied in combination with insulin. (1.1)
`------------------------DOSAGE AND ADMINISTRATION----------------------
`•
`Administer once daily with the evening meal. (2.1)
`•
`Individualize the starting dose based on the patient’s current regimen
`then adjust the dose based on effectiveness and tolerability. (2.1)
`Do not exceed a daily dose of 5 mg saxagliptin/2000 mg metformin HCl
`extended-release. (2.1)
`Swallow whole. Never crush, cut, or chew. (2.1)
`Limit the saxagliptin dose to 2.5 mg daily for patients also taking strong
`cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). (2.2, 7.1)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets:
`•
`5 mg saxagliptin/500 mg metformin HCl extended-release (3)
`•
`5 mg saxagliptin/1000 mg metformin HCl extended-release (3)
`•
`2.5 mg saxagliptin/1000 mg metformin HCl extended-release (3)
`------------------------------CONTRAINDICATIONS-------------------------------
`•
`Renal impairment. (4)
`•
`Hypersensitivity to metformin hydrochloride. (4)
`• Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`
`•
`•
`
`3
`4
`5
`
`FULL PRESCRIBING INFORM TION: CONTENTS* A
`
`WARNING: LACTIC ACIDOSIS
`1
`INDICATIONS AND USAGE
`1.1
`Important Limitations of Use
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`2.2
`Strong CYP3A4/5 Inhibitors
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Lactic Acidosis
`5.2
`Assessment of Renal Function
`5.3
`Impaired Hepatic Function
`5.4
`Vitamin B12 Concentrations
`5.5
`Alcohol Intake
`5.6
`Surgical Procedures
`5.7
`Change in Clinical Status of Patients with Previously
`Controlled Type 2 Diabetes
`5.8
`Use with Medications Known to Cause Hypoglycemia
`5.9
`Concomitant Medications Affecting Renal Function or
`Metformin Disposition
`
`Reference ID: 2860284
`
`1
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Temporarily discontinue in patients undergoing radiologic studies with
`intravascular administration of iodinated contrast materials. (4, 5.1, 5.10)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`•
`Lactic acidosis: Warn patients against excessive alcohol intake.
`KOMBIGLYZE XR not recommended in hepatic impairment and
`contraindicated in renal impairment. Ensure normal renal function
`before
`initiating and at
`least annually
`thereafter. Temporarily
`discontinue KOMBIGLYZE XR for surgical procedures necessitating
`restricted intake of food and fluids. (4, 5.1, 5.2, 5.3, 5.6, 5.9)
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`Measure hematological parameters annually. (5.4, 6.1)
`insulin secretagogue (e.g.,
`Hypoglycemia: When used with an
`sulfonylurea), a lower dose of the insulin secretagogue may be required
`to reduce the risk of hypoglycemia. (5.8)
`• Macrovascular outcomes: No conclusive evidence of macrovascular risk
`reduction with KOMBIGLYZE XR or any other antidiabetic drug.
`(5.12)
`-------------------------------ADVERSE REACTIONS------------------------------
`•
`Adverse reactions reported in >5% of patients treated with metformin
`extended-release and more commonly than in patients treated with
`placebo are: diarrhea and nausea/vomiting. (6.1)
`Adverse reactions reported in ≥5% of patients treated with saxagliptin
`and more commonly than in patients treated with placebo are: upper
`respiratory tract infection, urinary tract infection, and headache. (6.1)
`Adverse reactions reported in ≥5% of treatment-naive patients treated
`with coadministered saxagliptin and metformin and more commonly
`than in patients treated with metformin alone are: headache and
`nasopharyngitis.
`Hypersensitivity-related events (e.g., urticaria, facial edema) were
`reported more commonly in patients treated with saxagliptin than in
`patients treated with placebo. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`--------------------------------DRUG INTERACTIONS-----------------------------
`•
`Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole)
`significantly
`increases
`saxagliptin
`concentrations.
`Limit
`KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily. (2.2, 7.1)
`Cationic drugs eliminated by renal tubular secretion may reduce
`metformin elimination: use with caution. (5.9, 7.2)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`•
`No adequate and well-controlled studies in pregnant women. (8.1)
`•
`Safety and effectiveness have not been established in children. (8.4)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`•
`
`Revised: 11/2010
`
`5.10 Radiologic Studies with Intravascular Iodinated Contrast
`Materials
`5.11 Hypoxic States
`5.12 Macrovascular Outcomes
`A VERSE REACTIONS
`D
`6.1
`Clinical Trials Experience
`DRUG INTERACTIONS
`7.1
`Strong Inh bitors of CYP3A4/5 Enzymes
`7.2
`Cationic Drugs
`7.3
`Use with Other Drugs
` POPULATIONS
`USE IN SPECIFI
`C
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Actio n
`12.2 Pharmacodynami s c
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`6
`7
`
`8
`
`10
`11
`12
`
`13
`
`

`

`16
`17
`
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1
`Instructions
` Sections or subsections omitted from the full prescribing information
`are not listed
`
` *
`
`14
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology
`CLINICAL STUDIES
`14.1 Coadministration of Saxagliptin with Metformin
`Immediate-Release in Treatment-Naive Patients
`14.2 Addition of Saxagliptin to Metformin Immediate-Release
`
`Reference ID: 2860284
`
`2
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: LACTIC ACIDOSIS
`
`Lactic acidosis is a rare, but serious, complication that can occur due to metformin
`accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol
`intake, hepatic impairment, renal impairment, and acute congestive heart failure.
`
`The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such
`as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific
`abdominal distress.
`
`Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
`
`If acidosis is suspected, KOMBIGLYZE XR should be discontinued and the patient
`hospitalized immediately. [See Warnings and Precautions (5.1).]
`
`1
`
`INDICATIONS AND USAGE
`
`KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is
`appropriate. [See Clinical Studies (14).]
`
`1.1
`
`Important Limitations of Use
`
`KOMBIGLYZE XR should not be used for the treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis.
`
`KOMBIGLYZE XR has not been studied in combination with insulin.
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`
`The dosage of KOMBIGLYZE XR should be individualized on the basis of the patient’s current
`regimen, effectiveness, and tolerability. KOMBIGLYZE XR should generally be administered
`
`Reference ID: 2860284
`
`3
`
`

`

`
`once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side
`effects associated with metformin. The following dosage forms are available:
`
`• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/500 mg
`• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets
`5 mg/1000 mg
`• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets
`2.5 mg/1000 mg
`
`The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin
`and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin
`extended-release once daily with gradual dose escalation to reduce the gastrointestinal side
`effects due to metformin.
`
`In patients treated with metformin, the dose of KOMBIGLYZE XR should provide metformin at
`the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch
`from metformin immediate-release to metformin extended-release, glycemic control should be
`closely monitored and dosage adjustments made accordingly.
`
`Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be
`treated with KOMBIGLYZE XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are
`either metformin naive or who require a dose of metformin higher than 1000 mg should use the
`individual components.
`
`The maximum daily recommended dose is 5 mg for saxagliptin and 2000 mg for metformin
`extended-release.
`
`the safety and efficacy of
`No studies have been performed specifically examining
`KOMBIGLYZE XR in patients previously treated with other antihyperglycemic medications and
`switched to KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken
`with care and appropriate monitoring as changes in glycemic control can occur.
`
`Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed,
`cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated
`in the feces as a soft, hydrated mass that may resemble the original tablet.
`
`Reference ID: 2860284
`
`4
`
`

`

`
`2.2
`
`Strong CYP3A4/5 Inhibitors
`
`The maximum recommended dose of saxagliptin is 2.5 mg once daily when coadministered with
`strong cytochrome P450 3A4/5 (CYP3A4/5)
`inhibitors (e.g., ketoconazole, atazanavir,
`clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and
`telithromycin). For these patients, limit the KOMBIGLYZE XR dose to 2.5 mg/1000 mg once
`daily. [See Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical
`Pharmacology (12.3).]
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/500 mg tablets
`are light brown to brown, biconvex, capsule-shaped, film-coated tablets with “5/500” printed
`on one side and “4221” printed on the reverse side, in blue ink.
`
`• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/1000 mg
`tablets are pink, biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one
`side and “4223” printed on the reverse side, in blue ink.
`
`• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 2.5 mg/1000 mg
`tablets are pale yellow to light yellow, biconvex, capsule-shaped, film-coated tablets with
`“2.5/1000” printed on one side and “4222” printed on the reverse side, in blue ink.
`
`4
`
`CONTRAINDICATIONS
`
`KOMBIGLYZE XR is contraindicated in patients with:
`
`• Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women,
`or abnormal creatinine clearance) which may also result from conditions such as
`cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
`
`• Hypersensitivity to metformin hydrochloride.
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis
`should be treated with insulin.
`
`Reference ID: 2860284
`
`5
`
`

`

`
`KOMBIGLYZE XR should be temporarily discontinued in patients undergoing radiologic
`studies involving intravascular administration of iodinated contrast materials because use of such
`products may result in acute alteration of renal function [see Warnings and Precautions (5.10)].
`
`5
`
`5.1
`
`WARNINGS AND PRECAUTIONS
`
`Lactic Acidosis
`
`Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin
`accumulation during treatment with KOMBIGLYZE XR; when it occurs, it is fatal in
`approximately 50% of cases. Lactic acidosis may also occur in association with a number of
`pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue
`hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels
`(>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an
`increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis,
`metformin plasma levels >5 µg/mL are generally found.
`
`The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very
`low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000
`patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there
`were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients
`with significant renal
`insufficiency,
`including both
`intrinsic renal disease and renal
`hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and
`multiple concomitant medications. Patients with congestive heart
`failure
`requiring
`pharmacologic management, in particular those with unstable or acute congestive heart failure
`who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk
`of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of
`lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function
`in patients taking metformin and by use of the minimum effective dose of metformin. In
`particular, treatment of the elderly should be accompanied by careful monitoring of renal
`function. Metformin treatment should not be initiated in patients ≥80 years of age unless
`measurement of creatinine clearance demonstrates that renal function is not reduced, as these
`patients are more susceptible to developing lactic acidosis. In addition, metformin should be
`promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or
`sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate,
`metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic
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`disease. Patients should be cautioned against excessive alcohol intake when taking metformin
`since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In
`addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast
`study and for any surgical procedure [see Warnings and Precautions (5.2, 5.5, 5.6, 5.10)].
`
`The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such
`as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal
`distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with
`more marked acidosis. The patient and the patient’s physician must be aware of the possible
`importance of such symptoms and the patient should be instructed to notify the physician
`immediately if they occur [see Warnings and Precautions (5.11)]. Metformin should be
`withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if
`indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a
`patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are
`common during initiation of therapy, are unlikely to be drug related. Later occurrence of
`gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
`
`Levels of fasting venous plasma lactate above the upper limit of normal, but less than 5 mmol/L,
`in patients taking metformin do not necessarily indicate impending lactic acidosis and may be
`explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous
`physical activity, or technical problems in sample handling. [See Warnings and Precautions
`(5.7).]
`
`Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking
`evidence of ketoacidosis (ketonuria and ketonemia).
`
`Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with
`lactic acidosis who is taking metformin, the drug should be discontinued immediately and
`general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable
`(with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt
`hemodialysis is recommended to correct the acidosis and remove the accumulated metformin.
`Such management often results
`in prompt reversal of symptoms and recovery [see
`Contraindications (4) and Warnings and Precautions (5.5, 5.6, 5.9, 5.10, 5.11)].
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`5.2
`
`Assessment of Renal Function
`
`Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and
`lactic acidosis increases with the degree of impairment of renal function. Therefore,
`KOMBIGLYZE XR is contraindicated in patients with renal impairment [see Contraindications
`(4)].
`
`Before initiation of KOMBIGLYZE XR, and at least annually thereafter, renal function should
`be assessed and verified as normal. In patients in whom development of renal impairment is
`anticipated
`(e.g., elderly),
`renal
`function should be assessed more
`frequently and
`KOMBIGLYZE XR discontinued if evidence of renal impairment is present.
`
`5.3
`
`Impaired Hepatic Function
`
`Metformin use in patients with impaired hepatic function has been associated with some cases of
`lactic acidosis. Therefore, KOMBIGLYZE XR is not recommended in patients with hepatic
`impairment.
`
`5.4
`
`Vitamin B12 Concentrations
`
`In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of
`previously normal serum vitamin B12 levels, without clinical manifestations, was observed in
`approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption
`from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and
`appears
`to be rapidly reversible with discontinuation of metformin or vitamin B12
`supplementation. Measurement of hematologic parameters on an annual basis is advised in
`patients on KOMBIGLYZE XR and any apparent abnormalities should be appropriately
`investigated and managed [see Adverse Reactions (6.1)].
`
`Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to
`be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum
`vitamin B12 measurements at 2- to 3-year intervals may be useful.
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`5.5
`
`Alcohol Intake
`
`Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned
`against excessive alcohol intake while receiving KOMBIGLYZE XR.
`
`5.6
`
`Surgical Procedures
`
`Use of KOMBIGLYZE XR should be temporarily suspended for any surgical procedure (except
`minor procedures not associated with restricted intake of food and fluids) and should not be
`restarted until the patient’s oral intake has resumed and renal function has been evaluated as
`normal.
`
`5.7
`
`Change in Clinical Status of Patients with Previously
`Controlled Type 2 Diabetes
`
`A patient with type 2 diabetes previously well controlled on KOMBIGLYZE XR who develops
`laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should
`be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include
`serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and
`metformin levels. If acidosis of either form occurs, KOMBIGLYZE XR must be stopped
`immediately and other appropriate corrective measures initiated.
`
`5.8
`
`Use with Medications Known to Cause Hypoglycemia
`
`Saxagliptin
`
`Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, when used in
`combination with saxagliptin, a lower dose of the insulin secretagogue may be required to reduce
`the risk of hypoglycemia. [See Adverse Reactions (6.1).]