`
`
`
`
`
`thereafter. Temporarily
`least annually
`initiating and at
`before
`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)
`Acute Pancreatitis: If pancreatitis is suspected, promptly discontinue
`KOMBIGLYZE XR. (5.2)
`Heart Failure: Consider the risks and benefits of KOMBIGLYZE XR in
`patients who have known risk factors for heart failure. Monitor patients
`for signs and symptoms. (5.3)
`Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels.
`Measure hematological parameters annually. (5.6, 6.1)
`Hypoglycemia: In the saxagliptin add-on to sulfonylurea, add-on to
`insulin, and add-on to metformin plus sulfonylurea trials, confirmed
`hypoglycemia was reported more commonly in patients treated with
`saxagliptin compared
`to placebo. When used with an
`insulin
`secretagogue (e.g., sulfonylurea) or insulin, a lower dose of the insulin
`secretagogue or insulin may be required to minimize the risk of
`hypoglycemia. (5.10, 6.1)
`Hypersensitivity-Related Events (e.g., urticaria, facial edema): More
`common in patients treated with saxagliptin than in patients treated with
`placebo; and postmarketing reports of serious hypersensitivity reactions,
`such as anaphylaxis, angioedema, and exfoliative skin conditions in
`patients treated with saxagliptin. Promptly discontinue KOMBIGLYZE
`XR, assess for other potential causes, institute appropriate monitoring
`and treatment, and initiate alternative treatment for diabetes. (5.14, 6.1,
`6.2)
`Arthralgia: Severe and disabling arthralgia has been reported in patients
`taking DPP4 inhibitors. Consider as a possible cause for severe joint
`pain and discontinue drug if appropriate. (5.15)
` Macrovascular Outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction with
`KOMBIGLYZE XR or any other antidiabetic drug. (5.16)
`
`
`
`
`
`
`
`------------------------------ 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. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800-236-9933 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. (5.11, 7.2)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`No adequate and well-controlled studies in pregnant women. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 4/2016
`
`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 hydrochloride
`extended-release) tablets, for oral use
`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)
`respiratory distress,
`Symptoms
`include malaise, myalgias,
`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)
`
`
`
`
`
`
`
`----------------------------- RECENT MAJOR CHANGES -----------------------
`Warnings and Precautions
`Pancreatitis (5.2)
`Heart Failure (5.3)
`
`4/2016
`4/2016
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`KOMBIGLYZE XR is a combination of saxagliptin, a dipeptidyl peptidase-4
`(DPP4) inhibitor, and metformin, a biguanide, 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)
`Limitations of Use:
`Not used for the treatment of type 1 diabetes mellitus or diabetic
`
`ketoacidosis. (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 dosage based on effectiveness and tolerability. (2.1)
`Do not exceed a daily dosage of 5 mg saxagliptin/2000 mg metformin
`
`HCl extended-release. (2.1)
`Swallow whole. Never crush, cut, or chew. (2.1)
`
`Limit the saxagliptin dosage 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)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Lactic Acidosis: Warn patients against excessive alcohol intake.
`
`KOMBIGLYZE XR is not recommended in hepatic impairment and
`contraindicated in renal impairment. Ensure normal renal function
`
`Reference ID: 3912436
`
`1
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING LACTIC ACIDOSIS
`1 INDICATIONS AND USAGE
`1.1 Limitation of Use
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`
`2.2 Dosage Adjustments with Concomitant Use of Strong CYP3A4/5
`
`Inhibitors
`
`2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or
`
`with Insulin
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`
`5.2 Pancreatitis
`
`5.3 Heart Failure
`
`5.4 Assessment of Renal Function
`
`5.5 Impaired Hepatic Function
`
`5.6 Vitamin B12 Concentrations
`
`5.7 Alcohol Intake
`
`5.8 Surgical Procedures
`
`5.9 Change in Clinical Status of Patients with Previously Controlled Type
`
`2 Diabetes
`
`5.10 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
`5.11 Concomitant Medications Affecting Renal Function or Metformin
`
`Disposition
`
`5.12 Radiologic Studies with Intravascular Iodinated Contrast Materials
`
`5.13 Hypoxic States
`
`5.14 Hypersensitivity Reactions
`
`5.15 Severe and Disabling Arthralgia
`
`5.16 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1 Strong Inhibitors of CYP3A4/5 Enzymes
`
`7.2 Cationic Drugs
`
`7.3 Use with Other Drugs
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
`14.1 Glycemic Efficacy Trials
`
`14.2 Cardiovascular Safety Trial
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`2
`
`Reference ID: 3912436
`
`
`
`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 Limitation of Use
`KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`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.
`
`3
`
`
`Reference ID: 3912436
`
`
`
`In patients treated with metformin, the dosage 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 dosage is 5 mg for saxagliptin and 2000 mg for metformin extended-
`release.
`
`No studies have been performed specifically examining the safety and efficacy of 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.
`
`2.2 Dosage Adjustments with Concomitant Use of Strong CYP3A4/5 Inhibitors
`The maximum recommended dosage 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 dosage to 2.5 mg/1000 mg once daily [see Dosage and Administration (2.1), Drug
`Interactions (7.1), and Clinical Pharmacology (12.3)].
`
`2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`When KOMBIGLYZE XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with
`insulin, a lower dosage of the insulin secretagogue or insulin may be required to minimize the risk of
`hypoglycemia [see Warnings and Precautions (5.10)].
`
`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
`
`Reference ID: 3912436
`
`
`
`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 (MI), and septicemia.
` Hypersensitivity to metformin hydrochloride.
` 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 (5.14) and
`Adverse Reactions (6.2)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 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 disease. Patients should be
`cautioned against excessive alcohol intake when taking metformin since alcohol potentiates the effects of
`5
`
`
`Reference ID: 3912436
`
`
`
`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
`(5.4, 5.7, 5.8, 5.12)].
`
`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 (5.13)]. 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 (5.9)].
`
`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 (5.7, 5.8, 5.11, 5.12,
`5.13)].
`
`5.2 Pancreatitis
`There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. In a
`cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease
`(ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were
`confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 9 of 8173 (0.1%) receiving
`placebo . Preexisting risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving
`saxagliptin and in 100% (9/9) of those patients receiving placebo.
`
`After initiation of KOMBIGLYZE XR, observe patients 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 for the development of
`pancreatitis while using KOMBIGLYZE.
`
`6
`
`
`Reference ID: 3912436
`
`
`
`5.3 Heart Failure
`In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors
`for ASCVD (SAVOR trial), more patients randomized to ONGLYZA (289/8280, 3.5%) were hospitalized
`for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event
`analysis the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard
`Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal
`impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment.
`
`Consider the risks and benefits of KOMBIGLYZE XR prior to initiating treatment in patients at a higher
`risk for heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise
`patients of the characteristic symptoms of heart failure, and to immediately report such symptoms. If heart
`failure develops, evaluate and manage according to current standards of care and consider discontinuation
`of KOMBIGLYZE XR.
`
`5.4 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.
`
`5.5 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.
`
`5.6 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.
`
`7
`
`
`Reference ID: 3912436
`
`
`
`5.7 Alcohol Intake
`Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against
`excessive alcohol intake while receiving KOMBIGLYZE XR.
`
`5.8 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.
`
`5.9 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.
`
`5.10 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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.3)].
`
`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.
`
`5.11 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.
`
`8
`
`
`Reference ID: 3912436
`
`
`
`5.12 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.
`
`5.13 Hypoxic States
`Cardiovascular collapse (shock), acute congestive heart failure, acute MI, 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.
`
`5.14 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.
`
`5.15 Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP4 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 DPP4 inhibitor. Consider DPP4
`inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
`
`5.16 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`KOMBIGLYZE XR or any other antidiabetic drug.
`
`6 ADVERSE REACTIONS
`
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`• Pancreatitis [see Warnings and Precautions (5.2)]
`
`• Heart Failure [see Warnings and Precautions (5.3)]
`
`• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.10)]
`9
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`Reference ID: 3912436
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`
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`• Hypersensitivity Reactions [see Warnings and Precautions (5.14)]
`
`6.1 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.
`
`Adverse Reactions in Efficacy Trials
`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
`
`The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies (14)].
`These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of
`exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years or
`older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4%
`Asian, Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes
`for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or
`mildly impaired (eGFR≥60mL/min/1.73m2) in 91% of these patients.
`
`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin.
`These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least
`5% of patients treated with saxagliptin.
`
`Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with
`Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo
`
`% of Patients
`
`Placebo
`Saxagliptin 5 mg
`N=799
`N=882
`7.6
`7.7
`Upper respiratory tract infection
`6.1
`6.8
`Urinary tract infection
`5.9
`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.
`
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`Reference ID: 3912436
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`In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin 5 mg versus
`placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%.
`None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of
`peripheral edema for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo were 3.6% and 2% versus 3%
`given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin, and 2.4% and
`1.2% versus 2.2% given as add-on therapy to glyburide.
`
`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 10 mg saxagliptin dosage is not an approved dosage.
`The incidence rate of fracture events in patients who received saxagliptin did not increase over time.
`Causality has not been established and nonclinical studi