`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)
`
`
`•
`
`
`•
`
`
`•
`
`11/2011
`11/2011
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage
`
`Important Limitations of Use (1.1)
`
`
`Contraindications (4)
`
`Warnings and Precautions
`
`
`11/2011
`
`Pancreatitis (5.2)
`
`
`
`11/2011
`Hypersensitivity Reactions (5.13)
`
`
`---------------------------INDICATIONS AND USAGE----------------------------
`
`
`KOMBIGLYZE XR is a dipeptidyl peptidase-4 (DPP4) 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)
`
`•
`
`Has not been studied in patients with a history of pancreatitis. (1.1, 5.2)
`
`
`
`
`•
`------------------------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)
`
`
`
`History of a serious hypersensitivity reaction (e.g., anaphylaxis,
`
`
`•
`angioedema, exfoliative skin conditions) to KOMBIGLYZE XR or
`
`saxagliptin. (4)
`
`
`•
`
`
`•
`
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`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
`
`
`3
`
`4
`
`5
`
`Reference ID: 3044280
`
`1
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`------------------------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 in patients undergoing radiologic
`
`
`studies with intravascular administration of iodinated contrast materials
`
`
`
`
`or any surgical procedures necessitating restricted intake of food and
`
`fluids. (4, 5.1, 5.3, 5.4, 5.7, 5.10, 5.11)
`
`
`
`There have been postmarketing reports of acute pancreatitis in patients
`
`
`
`taking saxagliptin. If pancreatitis is suspected, promptly discontinue
`
`
`
`KOMBIGLYZE XR. (5.2)
`
`
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`Measure hematological parameters annually. (5.5, 6.1)
`
`
`Hypoglycemia: When used with an
`insulin secretagogue (e.g.,
`
`
`sulfonylurea), a lower dose of the insulin secretagogue may be required
`
`
`
`to reduce the risk of hypoglycemia. (5.9)
`
`
`There have been postmarketing reports of serious hypersensitivity
`
`reactions, such as anaphylaxis, angioedema, and exfoliative skin
`
`
`
`conditions in patients treated with saxagliptin. In such cases, promptly
`
`
`discontinue KOMBIGLYZE XR, assess for other potential causes,
`
`
`institute appropriate monitoring and treatment, and initiate alternative
`
`
`treatment for diabetes. (5.13, 6.2)
`
`
`• Macrovascular outcomes: No conclusive evidence of macrovascular risk
`
`
`
`reduction with KOMBIGLYZE XR or any other antidiabetic drug.
`
`(5.14)
`-------------------------------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. (5.10, 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 Medication
`Guide
`
`
`•
`
`Revised: 11/2011
`
`
`5.1
`
`5.2
`
`5.3
`
`5.4
`
`5.5
`
`5.6
`
`5.7
`
`5.8
`
`5.9
`
`
`Lactic Acidosis
`
`Pancreatitis
`
`Assessment of Renal Function
`
`Impaired Hepatic Function
`
`
`Vitamin B12 Concentrations
`
`Alcohol Intake
`
`Surgical Procedures
`Change in Clinical Status of Patients with Previously
`
`Controlled Type 2 Diabetes
`
`Use with Medications Known to Cause Hypoglycemia
`
`2.0
`
`Approved
`
`v
`
`

`

`
`10
`
`11
`
`12
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`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
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1
`Instructions
`
`* Sections or subsections omitted from the full prescribing information
`
`
`are not listed
`
`
`13
`
`
`14
`
`
`16
`
`17
`
`
`
`
`6
`
`
`7
`
`
`8
`
`5.10 Concomitant Medications Affecting Renal Function or
`
`
`
`
`Metformin Disposition
`
`5.11 Radiologic Studies with Intravascular Iodinated Contrast
`
`
`
`Materials
`
`
`5.12 Hypoxic States
`
`
`5.13 Hypersensitivity Reactions
`
`
`5.14 Macrovascular Outcomes
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`
`
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`7.1
`Strong Inhibitors of CYP3A4/5 Enzymes
`
`
`
`7.2
`Cationic Drugs
`
`
`7.3
`Use with Other Drugs
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`Reference ID: 3044280
`
`2
`
`2.0
`
`Approved
`
`v
`
`

`

`
`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.
`
`
`KOMBIGLYZE XR 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 KOMBIGLYZE XR. [See Warnings and Precautions (5.2).]
`
`
`
`3
`
`Reference ID: 3044280
`
`2.0
`
`Approved
`
`v
`
`

`

`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`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
`
`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.
`4
`
`Reference ID: 3044280
`
`2.0
`
`Approved
`
`v
`
`

`

`
`
`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.
`
`
`
`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.
`
`
`5
`
`Reference ID: 3044280
`
`2.0
`
`Approved
`
`v
`
`

`

`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis
`
`
`
`
`should be treated with insulin.
`
`
`
`
`• History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin, such as
`
`
`anaphylaxis, angioedema, or exfoliative skin conditions. [See Warnings and Precautions
`
`(5.13) and Adverse Reactions (6.2).]
`
`
`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
`
`6
`
`Reference ID: 3044280
`
`2.0
`
`Approved
`
`v
`
`

`

`
`
`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
`
`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 (5.3, 5.6, 5.7, 5.11)].
`
`
`
`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 (5.12)]. 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
`
`(5.8).]
`
`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 (5.6, 5.7, 5.10, 5.11, 5.12)].
`
`
`7
`
`Reference ID: 3044280
`
`2.0
`
`Approved
`
`v
`
`

`

`
`5.2
`
`Pancreatitis
`
`
`There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After
`
`initiation of KOMBIGLYZE XR, patients should be observed carefully for signs and symptoms
`of pancreatitis. If pancreatitis is suspected, KOMBIGLYZE XR should promptly be discontinued
`
`and appropriate management should be initiated. It is unknown whether patients with a history of
`pancreatitis are at
`increased risk for
`the development of pancreatitis while using
`KOMBIGLYZE XR.
`
`
`
`5.3
`
`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.
`
`5.4
`
`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.
`
`5.5
`
`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
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`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.
`
`5.6
`
`
`
`Alcohol Intake
`
`Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned
`against excessive alcohol intake while receiving KOMBIGLYZE XR.
`
`5.7
`
`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.
`
`
`
`5.8
`
`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.
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`5.9
`
`
`
`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).]
`
`
`
`Metformin hydrochloride
`
`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, or during concomitant use with other glucose-lowering
`
`
`agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished
`patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly
`
`susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly
`
`
`and in people who are taking beta-adrenergic blocking drugs.
`
`
`
`5.10
`
`Concomitant Medications Affecting Renal Function or
`Metformin Disposition
`
`
`Concomitant medication(s) that may affect renal function or result in significant hemodynamic
`
`change or may interfere with the disposition of metformin, such as cationic drugs that are
`eliminated by renal tubular secretion [see Drug Interactions (7.2)], should be used with caution.
`
`
`
`5.11
`
`Radiologic Studies with Intravascular 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.
`
`
`Therefore, in patients in whom any such study is planned, KOMBIGLYZE XR should be
`temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours
`
`subsequent to the procedure and reinstituted only after renal function has been re-evaluated and
`found to be normal.
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`
`
`Hypoxic States
`
`
`Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and
`
`
`other conditions characterized by hypoxemia have been associated with lactic acidosis and may
`
`also cause prerenal azotemia. When such events occur in patients on KOMBIGLYZE XR
`
`therapy, the drug should be promptly discontinued.
`
`5.13
`
`
`
`Hypersensitivity Reactions
`
`
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated
`
`
`with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin
`
`conditions. Onset of these reactions occurred within the first 3 months after initiation of
`
`treatment with saxagliptin, with some reports occurring after 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. [See Adverse Reactions
`
`(6.2).]
`
`Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4)
`
`inhibitor because it is unknown whether such patients will be predisposed to angioedema with
`KOMBIGLYZE XR.
`
`5.14
`
`Macrovascular Outcomes
`
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with KOMBIGLYZE XR or any other antidiabetic drug.
`
`6
`
`6.1
`
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`
`of another drug and may not reflect the rates observed in practice.
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`Monotherapy and Add-On Combination Therapy
`
`
`
`Metformin hydrochloride
`
`
`In placebo-controlled monotherapy
`trials of metformin extended-release, diarrhea and
`
`nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than
`
`in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for
`
`nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients
`
`treated with metformin extended-release.
`
`Saxagliptin
`
`In two placebo-controlled monotherapy trials of 24-week duration, patients were treated with
`saxagliptin 2.5 mg daily, saxagliptin 5 mg daily, and placebo. Three 24-week, placebo-
`controlled, add-on combination therapy trials were also conducted: one with metformin
`
`
`immediate-release, one with a thiazolidinedione (pioglitazone or rosiglitazone), and one with
`
`glyburide. In these three trials, patients were randomized to add-on therapy with saxagliptin
`2.5 mg daily, saxagliptin 5 mg daily, or placebo. A saxagliptin 10 mg treatment arm was
`included in one of the monotherapy trials and in the add-on combination trial with metformin
`
`immediate-release.
`
`In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the
`
`
`two monotherapy trials, the add-on to metformin immediate-release trial, the add-on to
`
`thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the overall incidence of adverse
`
`events in patients treated with saxagliptin 2.5 mg and saxagliptin 5 mg was similar to placebo
`
`(72.0% and 72.2% versus 70.6%, respectively). Discontinuation of therapy due to adverse events
`
`occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and
`placebo, respectively. The most common adverse events (reported in at least 2 patients treated
`with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with
`premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%,
`
`respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0%
`
`versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The
`
`adverse reactions in this pooled analysis reported (regardless of investigator assessment of
`causality) in ≥5% of patients treated with saxagliptin 5 mg, and more commonly than in patients
`
`treated with placebo are shown in Table 1.
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`Number (%) of Patients
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`
`
`Table 1:
`
`
`Adverse Reactions (Regardless of Investigator Assessment of
`
`
`Causality) in Placebo-Controlled Trials* Reported in ≥5% of
`Patients Treated with Saxagliptin 5 mg and More Commonly than
`in Patients Treated with Placebo
`
`
`
`Placebo
`Saxagliptin 5 mg
`N=799
`N=882
`61 (7.6)
`68 (7.7)
`Upper respiratory tract infection
`
`
`49 (6.1)
`60 (6.8)
`Urinary tract infection
`47 (5.9)
`57 (6.5)
`Headache
`* The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with
`
`
`
`
`each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of
`
`glycemic rescue.
`
`In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction
`reported at a rate ≥5% and more commonly than in patients treated with placebo.
`
`
`In this pooled analysis, adverse reactions that were reported in ≥2% of patients treated with
`saxagliptin 2.5 mg or saxagliptin 5 mg and ≥1% more frequently compared to placebo included:
`
`
`sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7% versus
`0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).
`
`
`
`The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for
`
`saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The incidence rate of
`fracture events in patients who received saxagliptin did not increase over time. Causality has not
`
`been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on
`
`bone.
`
`An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic
`
`purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not
`
`known.
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`Adverse Reactions Associated with Saxagliptin Coadministered with Metformin
`
`
`Immediate-Release in Treatment-Naive Patients with Type 2 Diabetes
`
`
`Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality)
`
`in ≥5% of patients participating in an additional 24-week, active-controlled trial of
`
`coadministered saxagliptin and metformin in treatment-naive patients.
`
`
`
`Table 2:
`
`Coadminis