3217106
`HIGHLIGHTS OF PRESORIBING INFORMATION
`These highlights do not include all the information needed to use KOMBIGLYZE XR
`safely and effectively. See full prescribing infonnation for KOMBIGLYZE XR.
`KOMBIGLYZEP XR (saxagliptin and metlonnin hydrochloride extended-release)
`tablets, for oral use
`Initial U.S. Approval: 2010
`
`WARNING: LAUTIO AOIDOSIS
`see full prescribing infonnation for complete boxed warning.
`0 Lactic acidosis can occur due to metformin accumulation. The risk increases wittr
`conditions such as sepsis, dehydration, excess alcohol intake, hepatic impainnent,
`renal impaimrent, and acute congestive heart failure. 5.1)
`0 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)
`0 If acidosis is suspected, discontinue KOMBIGLYZE XR and hospitalize the patient
`
`immediately. (5.1)
`
`---------------------------- REOENT MAJOR CHANGES -----------------------------
`Warnings and Precautions
`4/2016
`Pancreatitis (5.2)
`4/2016
`Heart Failure (5.3)
`---------------------------- INDIOATIONS 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:
`0 Not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1.1)
`------------------------- DOSAGE AND ADMINISTRATION --------------------------
`0 Administer once daily with the evening meal. (2.1)
`0
`Individualize the starting dose based on the patient’s current regimen then adjust
`the dosage based on effectiveness and tolerability. (2.1)
`0 Do not exceed a daily dosage of 5 mg saxagliptin/2000 mg metformin HCI
`extended-release. (2.1)
`0 Swallow whole. Never crush, cut, or chew. (2.1)
`0 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:
`0
`5 mg saxagliptin/500 mg metformin HCI extended-release (3)
`0
`5 mg saxagliptin/1000 mg metformin HCI extended-release (3)
`0
`2.5 mg saxagliptin/1000 mg metformin HCI extended-release (3)
`-------------------------------OONTRAINDIOATIONS-------------------------------
`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)
`
`0
`
`---------------------------WARNINGS AND PREOAUTlONS-------------------------
`0 Lactic Acidosis: Wam patients against excessive alcohol intake. KOMBIGLYZE XR
`is 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)
`0 Pancreatitis: If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR. (5.2)
`0 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)
`lfitamin Biz Deficiency: Metformin may lower vitamin B12 levels. Measure
`hematological parameters annually. (5.6, 6.1)
`0 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)
`0 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)
`0 Artfrralgia: 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)
`0 Macrovascular Outcomes: There have been no clinical studies establishing
`conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any
`other antidiabetic dnrg. (5.16)
`-------------------------------ADVERSE REAOTlONS-------------------------------
`0 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)
`0 Adverse reactions reported in 25% 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)
`0 Adverse reactions reported in 25% 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)
`report SUSPEOTED ADVERSE REACTIONS,
`contact Astrazeneca at
`To
`1-8!!)-236-9933 or FDA at 1-8!!)-FDA-1088 or wvvw.fda.gov/medwatch.
`-------------------------------- DRUG INTERAOTIONS -----------------------------
`0 Coadministration with
`strong CYP3A4/5
`inhibitors
`(e.g.,
`ketoconazole)
`significantly increases saxagliptin concentrations. Umit KOMBIGLYZE XR dose to
`2.5 mg/1000 mg once daily. (2.2, 7.1)
`0 Cationic dnrgs eliminated by renal tubular secretion may reduce metformin
`elimination: use with caution. (5.11, 7.2)
`-------------------------- USE IN SPEOIFIO POPULATIONS --------------------------
`0 No adequate and well-controlled studies in pregnant women. (8.1)
`See 17 for PATIENT OOUNSEIJNG INFORMATION and Medication Guide.
`Revised: 04/2016
`
`2
`
`FULL PRESCRIBING INFORMATION: OONTENTS*
`.
`IIIIAIIII:IIIIIII(I.'I'AI-figi-I-ISIIAAIIIIIIIIIIISSAIEE
`I_I Limitation of Use
`DDSAGE AND ADMINISTRATION
`2_I Recommended Dosage
`22 Dosage Adiusimenis wiih concomitant Use of
`Strong CYP3A4/5 Inhibitors
`-
`-
`-
`IIEIIIJI-IIOSTIIEIII:/IrIr:rI::aIIvIr::Iecretagogue
`2-3
`DDSAGE FDIINIS AND S-IIIENG-IIIS
`3
`DDNTIIAINDIDATIDNS
`4
`5 WARNINGS AND PIIEDAII-I-IDNS
`5_I Laeiie Acidosis
`52 Pancreatitis
`5_3 Hean Faiiure
`5_4 Assessmem of Denai Function
`5.5 Impaired Hepatic Function
`5.6 lfrtamin 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 Concomrtant Medrcatrons Affecting Renal
`Functionior Metformin Disposition
`_
`5.12 Radrologrc Studres wrth intravascular lodrnated
`5 13 fi°""aEs‘s"1'ai“""a‘s
`.
`ypoxrc
`a es
`_
`5.14 Hypersensitivity Reactions
`5.15 Severe and Drsablrng Arthralgra
`5.16 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1 Clrnical Triais Experience
`6.2 Postmarketrng Experience
`DRUG INTERAOTIONS
`7.1 Strong Inhrbrtors of CYP3A4/5 Enzymes
`7.2 Cationic Dnrgs
`7.3 Use with Other Drugs
`USE IN SPEOIFIO POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`
`6
`
`7
`
`8
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 OLINIOAL PHARMAOOLOGY
`12.1 Mechanism ofAction
`::“"”““°°flY"“}i”“°s
`.
`armaco rne cs
`13 NONOUNIOAL TOXIOOLOGY
`13.1 Carcinogenesis, Mutagenesis, impairment
`of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 OLINIOAL STUDIES
`14.1 Glycemic Efficacy Trials
`14.2 Cardiovascular Safety Trial
`16 HOW SUPPUED/STORAGE AND HANDLING
`17 PATIENT OOUNSELING INFORMATION
`
`* Sections or subsections omitted from the full
`prescribing information are not listed
`
`Page 1 Of 16
`
`Astraleneca Exhibit 2197
`
`Mylan v. Astraleneca
`lPR2015-01340
`
`AstraZeneca Exhibit 2197
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 16
`
`

`
`KOMBIGLYZEP XR (saxagliptin and metfonnin HCI extended-release)
`
`FULL PRESORIBING INFORMATION
`
`WARNING: LAOTIO AOIDOSIS
`Lactic acidosis is a rare, but serious, complication that can occur due to
`metfonnin accumulation. The risk increases with conditions such as sepsis,
`dehydration, excess alcohol intake, hepatic impainnent, renal impainnent,
`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 abnonnalities include low pH, increased anion gap, and elevated
`blood lactate.
`
`patient hospitalized immediately [see Warnings and Precautions (5.1)].
`
`If acidosis is suspected, KOMBIGLYZE XR should be discontinued and the
`
`INDIOATIONS AND USAGE
`1
`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 Ilse
`KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or
`diabetic ketoacidosis.
`2
`DOSAGE AND ADMINISTRATION
`
`0
`
`0
`
`Recommended Dosage
`2.1
`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:
`0
`KOMBIGLYZE XR (saxagliptin and metformin HCI extended-release) tablets
`5 mg/500 mg
`KOMBIGLYZE XR (saxagliptin and metformin HCI extended-release) tablets
`5 mg/1000 mg
`KOMBIGLYZE XR (saxagliptin and metformin HCI 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
`cnrshed, 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 Adiustments with concomitant Use of Strong OYP3A4l5
`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)].
`
`Page 2 of 16
`
`3
`0
`
`0
`
`0
`
`0
`0
`
`0
`
`DOSAGE FORMS AND STRENGTHS
`KOMBIGLYZE XR (saxagliptin and metformin HCI 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 HCI 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 HCI 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.
`OONTRAINDIOATIONS
`4
`KOMBIGLYZE XR is contraindicated in patients with:
`0
`Renal impairment (e.g., serum creatinine levels 21.5 mg/dL for men, 21 .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) andAdverse Reactions (6.2)].
`WARNINGS AND PRECAUTIONS
`5
`Lactic Acidosis
`5.1
`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 Iactate/
`pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin
`plasma levels >5 pg/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
`280 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 (5.4, 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.
`
`Page 2 of 16
`
`

`
`KOMBIGLYZEP XR (saxagliptin and metfonnin HCI extended-release)
`
`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 mUmin 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
`Pancreatilis
`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.
`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 saxagliptin
`(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.
`Impaired Hepatic Function
`5.5
`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.
`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.
`
`Page 3 of 16
`
`surgical Procedures
`5.8
`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, pynlvate, and metformin levels. If acidosis of either
`form occurs, KOMBIGLYZE XR must be stopped immediately and other appropriate
`corrective measures initiated.
`
`Hypoglycemia with concomitant Use of sulfonylurea or Insulin
`5.10
`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 andAdministration (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 Metlonnin
`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.
`5.12
`Radiologic Studies with lntravascular lodinated contrast Materials
`lntravascular 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.
`
`Hypoxic States
`5.13
`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 dnrg 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.
`
`Page 3 of 16
`
`

`
`KOMBIGLYZEP XR (saxagliptin and metfonnin HCI extended-release)
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described below or elsewhere in the
`prescribing information:
`0 Pancreatitis [see Warnings and Precautions (5.2)]
`0 Heart Failure [see Warnings and Precautions (5.3)]
`0 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and
`Precautions (5. 10)]
`0 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 orAfrican 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 (eGFR260mL/min/1.73m?) 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 Tria|s* Reported in 25%
`of Patients Treated with saxagliptin 5 mg and More commonly
`than in Patients Treated with Placebo
`% of Patients
`saxagliptin 5 mg
`N=882
`
`Placebo
`N:
`
`7_6
`7]
`Ui[:l[f):£t£§:pIrat0l'y tract
`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 25% and more commonly than in patients treated with
`placebo.
`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 dnrg 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 studies have not demonstrated adverse effects of
`saxagliptin on bone.
`idiopathic
`of
`An
`event of
`thrombocytopenia, consistent with a diagnosis
`thrombocytopenic purpura, was observed in the clinical program. The relationship of
`this event to saxagliptin is not known.
`Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8%
`of subjects receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively.
`The most common adverse reactions (reported in at least 2 subjects trea