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
`
`
`
`
`
`•
`
`
`
`•
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`
`
`•
`
`
`•
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`•
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`•
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`
`
` 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,
`include malaise, myalgias,
`Symptoms
`
`
` somnolence, and nonspecific abdominal distress.
`increasing
`
` Laboratory abnormalities include low pH, increased anion gap, and
`
`
`
`
`
`
`
` elevated blood lactate. (5.1)
`
`
` If acidosis is suspected, discontinue KOMBIGLYZE XR and
`
` hospitalize the patient immediately. (5.1)
`
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
`
`KOMBIGLYZE XR is a 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 for treatment of type 1 diabetes or diabetic ketoacidosis. (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 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
`
`
`
`before
`least annually
`thereafter. Temporarily
`initiating and at
`
`
`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 (postmarketing reports): If pancreatitis is suspected,
`
`
`
`
`promptly discontinue KOMBIGLYZE XR. (5.2, 6.2)
`
` Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels.
`
`
` Measure hematological parameters annually. (5.5, 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. (5.9, 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. (5.13, 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. (5.14)
`
`
`
`
`
` • Macrovascular Outcomes: No conclusive evidence of macrovascular
`
`
`
` risk reduction with KOMBIGLYZE XR or any other antidiabetic drug.
`
`
` (5.15)
`
`
`
`
`
`•
`
`
`
`•
`
`
`
`
`•
`
`
`•
`
`
`
`
`•
`
`
`
`------------------------------ 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)
`
`
`
`
`•
`
`concentrations.
`increases
`Limit
`saxagliptin
`significantly
`
`
`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)
`
`
`
`•
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`•
`
`
`
`Revised: 8/2015
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: LACTIC ACIDOSIS
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Limitations 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
`
`Reference ID: 3812564
`
`
`
`5.3 Assessment of Renal Function
`
`
`5.4 Impaired Hepatic Function
`
`
`5.5 Vitamin B12 Concentrations
`
`
`
`5.6 Alcohol Intake
`
`
`5.7 Surgical Procedures
`
`5.8 Change in Clinical Status of Patients with Previously Controlled Type
`
`
`
`2 Diabetes
`
`
`5.9 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
`
`
`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 Severe and Disabling Arthralgia
`
`
`
`
`

`

`5.15 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
`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 Coadministration of Saxagliptin with Metformin Immediate-Release
`in Treatment-Naive Patients
`14.2 Addition of Saxagliptin to Metformin Immediate-Release
`14.3 Saxagliptin Add-On Combination Therapy with Metformin
`Immediate-Release versus Glipizide Add-On Combination Therapy with
`Metformin Immediate-Release
`14.4 Saxagliptin Add-On Combination Therapy with Insulin (with or
`without Metformin Immediate-Release)
`14.5 Saxagliptin Add-On Combination Therapy with Metformin plus
`Sulfonylurea
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed
`
`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 should not be used for the treatment of type 1 diabetes mellitus or diabetic
`
`ketoacidosis.
`
`
`
`
`
`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)].
`
`
`
`
`
` 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
`
`
`Reference ID: 3812564
`
`

`

`
`
`
`
` 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 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 (5.9)].
`
`Reference ID: 3812564
`
`

`

`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
` • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/500 mg tablets are light
`
`
`
`
`
` brown to brown, biconvex, capsule-shaped, film-coated tablets with “5/500” printed on one side and
`
`
` “4221” printed on the reverse side, in blue ink.
`
`
` • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/1000 mg tablets are pink,
`
`
` biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one side and “4223” printed on
`
`
`
` the reverse side, in blue ink.
` • KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 2.5 mg/1000 mg tablets are pale
`
`
`
`
` yellow to light yellow, biconvex, capsule-shaped, film-coated tablets with “2.5/1000” printed on one
`
`
`
` side and “4222” printed on the reverse side, in blue ink.
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` KOMBIGLYZE XR is contraindicated in patients with:
`
`
`
` • Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or
`
`
`
`
`
`
`
`
`
`
` abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse
`
` (shock), acute myocardial infarction, and septicemia.
`
`
` • Hypersensitivity to metformin hydrochloride.
`
`
`
` • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
`
`
`
`
` treated with insulin.
` • 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 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
`
`
`
`
`Reference ID: 3812564
`
`

`

`
`
`
`
` 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
`
`
`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)].
`
`
`Reference ID: 3812564
`
`

`

`
`
`
` 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 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.
`
`
`
`Reference ID: 3812564
`
`

`

`
`
` 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.
`
`
`
`
`
` 5.9 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)].
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`
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`
`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.
`
`
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`
`
` 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.
`
`
`
`Reference ID: 3812564
`
`

`

`
`
` 5.12 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 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.
`
`
`
`
`
`
` 5.15 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
`
`
`
` 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 with Monotherapy and with 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
`
`Reference ID: 3812564
`
`

`

`
`
` 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. The 10 mg saxagliptin dosage is not an approved dosage.
`
`
`
`
`
`
`
`
` In a pre-specified 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% 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.
`
`
`
` Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients