7/29/2016
`
`Adult Type 2 Diabetes Mellitus Treatment | KOMBIGLYZEXR­HCP.com
`
`DPP-4 Inhibitors: ONGLYZA® (saxagliptin)
`
`KOMBIGLYZE® XR (saxagliptin and metformin HCl extended-release) tablets
`
`Our Type 2 Diabetes Portfolio »
`
`Important Safety Information | Prescribing Information, including Boxed WARNING
`Indication & Limitations of Use | Medication Guide
` |
`Prescribing Information, including Boxed WARNING |
`Indication | Medication Guide
`
` |
`
`Search
`For US Health Care Professionals
`Share
`Go to Patient Site
`Share
`
`MENU
`Register
`Important Safety Information for KOMBIGLYZE XR
`
`WARNING: LACTIC ACIDOSIS
`Lactic acidosis is a rare, but serious, complication that can occur...Read More due to metformin
`accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol
`intake,...Read More...Read More hepatic impairment, renal impairment, and acute congestive heart
`failure.
`
`A TREATMENT FOR ADULTS WITH TYPE 2 DIABETES MELLITUS, IN ADDITION TO DIET AND EXERCISE
`Expand
`KOMBIGLYZE XR IS NOT INDICATED FOR PATIENTS WITH TYPE 1 DIABETES MELLITUS OR DIABETIC KETOACIDOSIS
`
`Give them a KOMBIGLYZE XR
`
`When your patients need powerful A1C reductions right
`from the start
`VIEW DATA
`
`https://www.kombiglyzexr­hcp.com/
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`Mylan v. AstraZeneca
`IPR2015-01340
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`Adult Type 2 Diabetes Mellitus Treatment | KOMBIGLYZEXR­HCP.com
`
`DOSING
`INFORMATION
`
`PATIENT
`SAVINGS
`
`LEARN MORE »
`
`LEARN MORE »
`
`MECHANISM
`OF ACTION
`Learn how KOMBIGLYZE XR improves glycemic control by combining saxagliptin and metformin1
`
`FORMULARY
`COVERAGE »
`
`Important Safety Information for KOMBIGLYZE XR
`
`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 oǹen 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]
`
`Contraindications
`
`Renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or
`abnormal creatinine clearance)
`
`Hypersensitivity to metformin hydrochloride
`
`Acute or chronic metabolic acidosis, including diabetic ketoacidosis
`
`History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin (eg, anaphylaxis,
`
`https://www.kombiglyzexr­hcp.com/
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`Adult Type 2 Diabetes Mellitus Treatment | KOMBIGLYZEXR­HCP.com
`angioedema, or exfoliative skin conditions)
`
`Warnings and Precautions
`
`Lactic Acidosis:
`
`The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately
`0.03 cases/1000 patient-years). When it occurs, it is fatal in approximately 50% of cases. Reported
`cases of lactic acidosis have occurred primarily in diabetic patients with significant renal insufficiency
`
`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
`
`Lactic acidosis risk increases with the degree of renal dysfunction and patient age. The risk may be
`significantly decreased by use of minimum effective dose of metformin and regular monitoring of renal
`function. Careful renal monitoring is particularly important in the elderly. KOMBIGLYZE XR should not
`be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates
`that renal function is not reduced
`
`Withhold KOMBIGLYZE XR in the presence of any condition associated with hypoxemia, dehydration, or
`sepsis
`
`Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin,
`and in the SAVOR cardiovascular outcomes trial aǹer initiating saxagliptin. Aǹer initiating KOMBIGLYZE XR,
`observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly
`discontinue KOMBIGLYZE XR and initiate appropriate management. It is unknown whether patients with a
`history of pancreatitis are at increased risk of developing pancreatitis while using KOMBIGLYZE XR.
`
`Heart Failure: In SAVOR, a cardiovascular outcomes trial enrolling participants with established or
`multiple risk factors for atherosclerotic cardiovascular disease (ASCVD), more patients treated with
`saxagliptin were hospitalized for heart failure compared to placebo. Patients with a prior history of heart
`failure or renal impairment had a higher risk for hospitalization for heart failure. Consider the risks and
`benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor for signs and
`symptoms. If heart failure develops, initiate appropriate management and consider discontinuation of
`KOMBIGLYZE XR.
`
`Renal Function: Before initiation of KOMBIGLYZE XR, and at least annually thereaǹer, renal function should
`be assessed and verified as normal.
`
`Impaired Hepatic Function: KOMBIGLYZE XR is not recommended in patients with hepatic impairment.
`
`Vitamin B12 concentrations: Metformin may lower vitamin B12 levels. Measure hematological parameters
`annually.
`
`Alcohol Intake: Warn patients against excessive alcohol intake.
`
`Surgical Procedures: KOMBIGLYZE XR should be suspended for any surgical procedure (except minor
`procedures not associated with restricted intake of food and fluids), and should not be restarted until
`patient’s oral intake has resumed and renal function is normal.
`
`Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
`https://www.kombiglyzexr­hcp.com/
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`Adult Type 2 Diabetes Mellitus Treatment | KOMBIGLYZEXR­HCP.com
`Saxagliptin: When saxagliptin was used in combination with a sulfonylurea or with insulin,
`medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased
`over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose
`of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used
`in combination with KOMBIGLYZE XR
`
`Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual
`circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not
`compensated by caloric supplementation, during concomitant use with other glucose-lowering agents
`(such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated, or malnourished patients
`and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to
`hypoglycemic effects
`
`Radiological Studies with Iodinated Contrast Materials: Intravascular contrast studies with iodinated
`materials can lead to acute alteration of renal function and have been associated with lactic acidosis in
`patients receiving metformin. KOMBIGLYZE XR should be temporarily discontinued at the time of or prior
`to the procedure, and withheld for 48 hours aǹer the procedure and reinstituted only aǹer renal function
`is normal.
`
`Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients
`treated with saxagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of
`these reactions occurred within the first 3 months aǹer initiation of treatment with saxagliptin, with some
`reports occurring aǹer the first dose. If a serious hypersensitivity reaction is suspected, discontinue
`KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for
`diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown
`whether they will be predisposed to angioedema with KOMBIGLYZE XR.
`
`Arthralgia: There have been postmarketing reports of severe and disabling arthralgia in patients taking
`DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day
`to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of
`patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4
`inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if
`appropriate.
`
`Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of
`macrovascular risk reduction with KOMBIGLYZE XR or any other anti-diabetic drug.
`
`Adverse Reactions
`
`Adverse reactions reported in >5% of patients treated with metformin extended-release and more
`commonly than in patients treated with placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting
`(6.5% vs 1.5%)
`
`Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in
`patients treated with placebo were: upper respiratory tract infection (7.7% vs 7.6%), urinary tract
`infection (6.8% vs 6.1%), and headache (6.5% vs 5.9%)
`
`Adverse reactions reported in ≥5% of treatment-naïve patients treated with coadministered
`saxagliptin and metformin immediate-release (IR) and more commonly than in patients treated with
`metformin IR alone were: headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%)
`
`https://www.kombiglyzexr­hcp.com/
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`Adult Type 2 Diabetes Mellitus Treatment | KOMBIGLYZEXR­HCP.com
`Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg
`compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%,
`respectively). Among the patients using insulin with metformin, the incidence of confirmed
`hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed hypoglycemia was reported
`more commonly with saxagliptin 5 mg compared to placebo in the add-on to metformin plus
`sulfonylurea trial (1.6% and 0.0%, respectively)
`
`Drug Interactions
`
`Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, limit KOMBIGLYZE
`XR to 2.5 mg/1000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor (eg,
`atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
`saquinavir, and telithromycin)
`
`Use in Specific Populations
`
`Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women.
`KOMBIGLYZE XR should be used during pregnancy only if clearly needed. It is not known whether
`saxagliptin or metformin are secreted in human milk. Because many drugs are secreted in human
`milk, caution should be exercised when KOMBIGLYZE XR is administered to a nursing woman
`
`Pediatric Patients: Safety and effectiveness of KOMBIGLYZE XR in pediatric patients have not been
`established
`
`Indication and Limitations of Use
`
`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
`
`KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
`
`Please see US Full Prescribing Information
` for KOMBIGLYZE XR (5/500•5/1000•2.5/1000 mg tablets),
`including Boxed WARNING about lactic acidosis, and Medication Guide
`.
`
`You are encouraged to report negative side effects of prescription drugs to the FDA. Visit
`www.FDA.gov/medwatch or call 1-800-FDA-1088.1-800-FDA-1088.
`
`Reference:
`
`1. KOMBIGLYZE XR [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016.
`
`Contact Us
`AstraZeneca US Corporate Site
`Privacy Notice
`Legal Statement
`Site Map
`Prescribing Information
`
`https://www.kombiglyzexr­hcp.com/
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`Adult Type 2 Diabetes Mellitus Treatment | KOMBIGLYZEXR­HCP.com
`This product information is intended for US Health Care Professionals only.
`KOMBIGLYZE XR is a registered trademark of the AstraZeneca group of companies.
`©2016 AstraZeneca. All rights reserved. 1946515-3180022 Last Updated 4/16
`
`https://www.kombiglyzexr­hcp.com/
`
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`7/29/2016
`
`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`
`DPP-4 Inhibitors: ONGLYZA® (saxagliptin) KOMBIGLYZE® XR (saxagliptin and metformin HCl extended-release) tablets
`
`Our Type 2 Diabetes Portfolio »
`
`Important Safety Information | Prescribing Information, including Boxed WARNING
`Indication & Limitations of Use |
` |
`Medication Guide
` | Prescribing Information, including Boxed WARNING |
`Indication | Medication Guide
`
`For US Health Care Professionals
`Share
`Go to Patient Site
`Share
`
`Search
`
`MENU
`Register
`Important Safety Information for KOMBIGLYZE XR
`WARNING: LACTIC ACIDOSIS
`Lactic acidosis is a rare, but serious, complication that can occur...Read More due to metformin accumulation. The risk increases
`with conditions such as sepsis, dehydration, excess alcohol intake,...Read More...Read More hepatic impairment, renal impairment,
`and acute congestive heart failure.
`
`Expand
`A TREATMENT FOR ADULTS WITH TYPE 2 DIABETES MELLITUS, IN ADDITION TO DIET AND EXERCISE
`INITIAL DRUG THERAPY
`Demonstrated significant reductions in A1C levels and lower rates of hypoglycemia, in treatment-naïve patients
`Select a category below or scroll
` to learn more.
`
`A1C Reductions
`
`Hypoglycemic Events
`
`FPG-PPG Reductions
`
`Study Design
`
`START WITH SIGNIFICANCE
`A ONCE-DAILY TABLET THAT CAN HELP GET PATIENTS TO GOAL
`1
`
`PRIMARY END POINT
`Patients taking saxagliptin 5 mg + metformin IR achieved a 2.5% mean A1C reduction from baseline vs 2.0% mean A1C reduction from
`baseline with placebo + metformin IR
`1,2,a
`
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
`
`1/11
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`
`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`
`P<0.0001 vs metformin IR + placebo.
`
`a
`Least squares mean adjusted for baseline value.
`The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic
`2
`
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
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`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`7/29/2016
`criteria on metformin IR alone vs saxagliptin 5 mg + metformin IR was 10.1% vs 7.5%, respectively
`2
`
`A statistically significant number of treatment-naïve patients reached A1C goal of <7.0% at 24 weeks
`1,2,b-d
`
`SECONDARY END POINT
`
`of patients taking saxagliptin 5 mg + metformin immediate-release (IR) (n=307) achieved A1C
`<7.0% vs 41% taking placebo + metformin IR (n=314); P<0.05 vs placebo + metformin IR. Mean
`baseline A1C of 9.4% for both groups
`1,2,e
`
`b c
`
`Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.
`In this study, saxagliptin 5 mg and metformin IR were administered as separate tablets. Mean daily metformin IR doses at Week 24 were 1790 mg for saxagliptin 5 mg +
`2
`metformin IR and 1817 mg for placebo + metformin IR.
`P<0.05 vs placebo + metformin.
`Least squares mean adjusted for baseline value.
`
`d e
`
`Select Important Safety Information
`Contraindications
`
`Renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance)
`
`Hypersensitivity to metformin hydrochloride
`
`Acute or chronic metabolic acidosis, including diabetic ketoacidosis
`
`History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin (eg, anaphylaxis, angioedema, or exfoliative skin
`conditions)
`Adverse Reactions
`
`Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg compared to placebo in the add-on
`to insulin (with or without metformin) trial (5.3% and 3.3%, respectively). Among the patients using insulin with metformin, the
`incidence of confirmed hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed hypoglycemia was reported more
`commonly with saxagliptin 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial (1.6% and 0.0%,
`respectively)
`
`LOWER RATES OF REPORTED HYPOGLYCEMIA OVER 24 WEEKS
`1,2,f
`
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
`
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`
`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`
`In this study, saxagliptin 5 mg and metformin IR were administered as separate tablets.
`f
`Reported hypoglycemic events were a combination of reports of either signs or symptoms consistent with hypoglycemia with or without documented glucose levels or
`reported low glucose levels without symptoms. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to
`conclusively determine that all these reports reflect true hypoglycemia.
`Adverse reactions reported in ≥5% of patients treated with saxagliptin 5 mg + metformin IR and more commonly than metformin IR +
`placebo were headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%), respectively
`1,2
`
`Select Important Safety Information
`Adverse Reactions
`
`Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg compared to placebo in the add-on
`to insulin (with or without metformin) trial (5.3% and 3.3%, respectively). Among the patients using insulin with metformin, the
`incidence of confirmed hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed hypoglycemia was reported more
`commonly with saxagliptin 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial (1.6% and 0.0%,
`respectively)
`
`SIGNIFICANT REDUCTIONS IN FPG AND PPG
`1,2
`Saxagliptin 5 mg + metformin IR as initial combination therapy with metformin IR delivered statistically
`significant reductions in fasting plasma glucose (FPG) and postprandial glucose (PPG) vs placebo +
`metformin IR at 6 months
`1,2,g,h
`
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
`
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`
`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`
`P<0.05 vs placebo + metformin IR.
`
`GREATER REDUCTIONS WITH SAXAGLIPTIN 5 MG + METFORMIN IR
`2-HOUR PPG
`FPG
`-41 mg/dL
`-13 mg/dL
`(95% Cl: -57 mg/dL, -25 mg/dL)
`(95% Cl: -19 mg/dL, -6 mg/dL)
`
`P<0.05 vs placebo + metformin IR.
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
`
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`
`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`
`GREATER REDUCTIONS WITH SAXAGLIPTIN 5 MG + METFORMIN IR
`-13 mg/dL
`(95% Cl: -19 mg/dL, -6 mg/dL)
`
`P<0.05 vs placebo + metformin IR.
`
`GREATER REDUCTIONS WITH SAXAGLIPTIN 5 MG + METFORMIN IR
`-41 mg/dL
`(95% Cl: -57 mg/dL, -25 mg/dL)
`
`g h
`
`In these studies, saxagliptin 5 mg and metformin IR were administered as separate tablets.
`Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue.
`
`Select Important Safety Information
`Warnings and Precautions
`
`Surgical Procedures: KOMBIGLYZE XR should be suspended for any surgical procedure (except minor procedures not associated with
`restricted intake of food and fluids), and should not be restarted until patient’s oral intake has resumed and renal function is normal.
`
`Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
`Saxagliptin: When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause
`hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea
`or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia
`when used in combination with KOMBIGLYZE XR
`
`Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur
`when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, during concomitant use
`with other glucose-lowering agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated, or malnourished
`
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
`
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`

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`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`7/29/2016
`patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects
`
`STUDY DESIGN
`1,2
`Initial Drug Therapy
`
`Phase 3, multicenter, international, randomized, double-blind, active-controlled study
`
`Treatment-naïve A1C ≥8.0% and ≤12.0% (N=1306)
`
`Study Objective
`Evaluate the efficacy and safety of saxagliptin as initial combination therapy with metformin IR, in addition to diet and exercise,
`compared to metformin IR monotherapy in treatment-naïve patients.
`
`Primary Efficacy End Point
`A1C change from baseline at 6 months
`
`Secondary Efficacy End Points Included
`FPG change from baseline at 6 months
`
`Percentage of patients achieving A1C <7.0%
`
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
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`7/29/2016
`PPG change from baseline following an oral glucose tolerance test at 6 months
`
` 
`
`Study Length
`6 months
`
`Key Inclusion Criteria
`
`Demographic: Men and women age 18–77 years; patients had to be treatment-naïve
`
`Diagnosis: Type 2 diabetes mellitus (T2DM)
`
`A1C: ≥8.0% and ≤12.0%
`
`Fasting C-peptide: ≥1.0 ng/mL
`
`Body Mass Index: ≤40 kg/m
`
`2
`
` 
`
`Study Dosing
`
`Saxagliptin 5 mg  + metformin IR 500 mg*
`
`Saxagliptin 10 mg  + metformin IR 500 mg*
`
`Saxagliptin 10 mg  + placebo
`
`Metformin IR 500 mg* + placebo
`
`*
`Metformin IR dose was between 1000 and 2000 mg daily. Metformin IR was initiated at a starting dose of 500 mg daily, up-titrated to 1000 mg at Week 1, and
`therea퓒ퟕer up-titrated as tolerated to a maximum of 2000 mg daily based on FPG through Week 5.
`
`Primary Efficacy End Point
`A1C change from baseline at 6 months
`Secondary Efficacy End Points Included
`FPG change from baseline at 6 months
`
`Percentage of patients achieving A1C <7.0%
`
`PPG change from baseline following an oral glucose tolerance test at 6 months
`
`*Metformin IR dose was between 1000 and 2000 mg daily. Metformin IR was initiated at a starting dose of 500 mg daily, up-titrated to 1000 mg at Week 1, and
`therea퓒ퟕer up-titrated as tolerated to a maximum of 2000 mg daily based on FPG through Week 5.
`
`Primary Efficacy End Point
`A1C change from baseline at 6 months
`Secondary Efficacy End Points Included
`FPG change from baseline at 6 months
`
`Percentage of patients achieving A1C <7.0%
`
`PPG change from baseline following an oral glucose tolerance test at 6 months
`
`*Metformin IR dose was between 1000 and 2000 mg daily. Metformin IR was initiated at a starting dose of 500 mg daily, up-titrated to 1000 mg at Week 1, and
`therea퓒ퟕer up-titrated as tolerated to a maximum of 2000 mg daily based on FPG through Week 5.
`
`Important Safety Information for KOMBIGLYZE XR
`https://www.kombiglyzexr­hcp.com/efficacy/metformin­ir­and­initial­therapy.html
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`Efficacy | Saxagliptin 5 mg + Metformin IR Initial Therapy | A1C Levels
`Important Safety Information for KOMBIGLYZE XR
`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 o퓒ퟕen 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]
`
`Contraindications
`
`Renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance)
`
`Hypersensitivity to metformin hydrochloride
`
`Acute or chronic metabolic acidosis, including diabetic ketoacidosis
`
`History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin (eg, anaphylaxis, angioedema, or exfoliative skin
`conditions)
`
`Warnings and Precautions
`
`Lactic Acidosis:
`
`The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-
`years). When it occurs, it is fatal in approximately 50% of cases. Reported cases of lactic acidosis have occurred primarily in
`diabetic patients with significant renal insufficiency
`
`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
`
`Lactic acidosis risk increases with the degree of renal dysfunction and patient age. The risk may be significantly decreased by
`use of minimum effective dose of metformin and regular monitoring of renal function. Careful renal monitoring is particularly
`important in the elderly. KOMBIGLYZE XR should not be initiated in patients ≥80 years of age unless measurement of creatinine
`clearance demonstrates that renal function is not reduced
`
`Withhold KOMBIGLYZE XR in the presence of any condition associated with hypoxemia, dehydration, or sepsis
`
`Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin, and in the SAVOR
`cardiovascular outcomes trial a퓒ퟕer initiating saxagliptin. A퓒ퟕer initiating KOMBIGLYZE XR, observe patients carefully for signs and
`symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR and initiate appropriate management.
`It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using
`KOMBIGLYZE XR.
`
`Heart Failure: In SAVOR, a cardiovascular outcomes trial enrolling participants with established or multiple risk factors for
`atherosclerotic cardiovascular disease (ASCVD), more patients treated with saxagliptin were hospitalized for heart failure compared
`to placebo. Patients with a prior history of heart failure or renal impairment had a higher risk for hospitalization for heart failure.
`Consider the risks and benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor for signs and
`symptoms. If heart failure develops, initiate appropriate management and consider discontinuation of KOMBIGLYZE XR.
`
`Renal Function: Before initiation of KOMBIGLYZE XR, and at least annually therea퓒ퟕer, renal function should be assessed and verified
`as normal.
`
`Impaired Hepatic Function: KOMBIGLYZE XR is not recommended in patients with hepatic impairment.
`
`Vitamin B12 concentrations: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
`
`Alcohol Intake: Warn patients against excessive alcohol intake.
`
`Surgical Procedures: KOMBIGLYZE XR should be suspended for any surgical procedure (except minor procedures not associated
`with restricted intake of food and fluids), and should not be restarted until patient’s oral intake has resumed and renal function is
`
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`
`Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
`Saxagliptin: When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause
`hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a
`sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk
`of hypoglycemia when used in combination with KOMBIGLYZE XR
`
`Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could
`occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, during
`concomitant use with other glucose-lowering agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly,
`debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly
`susceptible to hypoglycemic effects
`
`Radiological Studies with Iodinated Contrast Materials: Intravascular contrast studies with iodinated materials can lead to acute
`alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. KOMBIGLYZE XR should
`be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours a퓒ퟕer the procedure and reinstituted
`only a퓒ퟕer renal function is normal.
`
`Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin,
`including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months
`a퓒ퟕer initiation of treatment with saxagliptin, with some reports occurring a퓒ퟕer the first dose. If a serious hypersensitivity reaction is
`suspected, discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for
`diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be
`predisposed to angioedema with KOMBIGLYZE XR.
`
`Arthralgia: There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time
`to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms
`upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug
`or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if
`appropriate.
`
`Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`with KOMBIGLYZE XR or any other anti-diabetic drug.
`
`Adverse Reactions
`
`Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients
`treated with placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%)
`
`Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with
`placebo were: upper respiratory tract infection (7.7% vs 7.6%), urinary tract infection (6.8% vs 6.1%), and headache (6.5% vs
`5.9%)
`
`Adverse reactions reported in ≥5% of treatment-naïve patients treated with coadministered saxagliptin and metformin
`immediate-release (IR) and more commonly than in patients treated with metformin IR alone were: headache (7.5% vs 5.2%)
`and nasopharyngitis (6.9% vs 4.0%)
`
`Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg compared to placebo in the
`add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively). Among the patients using insulin with
`metformin, the incidence of confirmed hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed hypoglycemia
`was reported more commonly with saxagliptin 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial
`(1.6% and 0.0%, respectively)
`
`Drug Interactions
`
`Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, limit KOMBIGLYZE XR to 2.5 mg/1000 mg
`once daily when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole,
`ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin)
`
`Use in Specific Populations
`
`Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. KOMBIGLYZE XR should
`be used during pregnancy only if clearly needed. It is not known whether saxagliptin or metformin are secreted in human milk.
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`Because many dr