HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use QTERN
` safely and effectively. See full prescribing information for QTERN.
`
`
`
`QTERN® (dapagliflozin and saxagliptin) tablets, for oral use
`
`
`
`
`
`Initial U.S. Approval: 2017
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`QTERN is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor and a
`
`
`
`
`dipeptidyl peptidase-4 (DPP-4) inhibitor combination product indicated as an
`
`
`
`
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`
`
`
`
`diabetes mellitus (T2DM) who have inadequate control with dapagliflozin or
`
`
`who are already treated with dapagliflozin and saxagliptin. (1, 14)
`
`Limitations of Use:
`
`
`
`
`• Is not indicated for the treatment of type 1 diabetes mellitus or diabetic
`
`
`ketoacidosis. (1)
`
`
`
`• Should only be used in patients who tolerate 10 mg dapagliflozin. (1)
`
`
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`The recommended dose of QTERN is a 10 mg dapagliflozin/5 mg saxagliptin
`
`
`tablet taken orally once daily in the morning with or without food. (2.1)
`
`
`
`• Assess renal function before initiation of therapy and periodically
`thereafter. Do not initiate QTERN if eGFR is below 60 mL/min/1.73 m2 .
`
`
`
`(2.2)
`• Discontinue QTERN if eGFR falls persistently below 60 mL/min/1.73 m2 .
`
`
`
`
`
`
`
`(2.2)
`
`
`
`
`• Do not coadminister QTERN with strong cytochrome P450 3A4/5
`
`
`inhibitors. (2.3, 7.1)
`
`
`
`
`• Tablet should be swallowed whole and not be split or cut.
`
`
`
`---------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`Tablet: 10 mg dapagliflozin/5 mg saxagliptin (3)
`
`
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`
`
`
`QTERN is contraindicated in patients with:
`
`
`• History of a serious hypersensitivity reaction to dapagliflozin or to
`
`saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin
`
`
`
`conditions. (4, 5.8, 6.2)
`• Moderate to severe renal impairment (eGFR <45 mL/min/1.73 m2),
`
`
`
`
`
`
`
`
`
`end-stage renal disease (ESRD), or patients on dialysis. (4)
`
`
`
`
`
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Pancreatitis: If pancreatitis is suspected, promptly discontinue QTERN. (5.1,
`
`
`
`
`
`6.2)
`Heart Failure: Consider the risks and benefits of QTERN in patients who
`
`
`
`
`
`have known risk factors for heart failure. Monitor patients for signs and
`
`symptoms. (5.2)
`Hypotension: Before initiating QTERN, assess volume status and correct
`
`
`
`
`hypovolemia in the elderly, in patients with renal impairment or low
`
`
`
`
`
`systolic blood pressure, and in patients on loop diuretics. Monitor for signs
`
`
`
`and symptoms during therapy. (5.3, 6.1)
`Ketoacidosis: Assess patients who present with signs and symptoms of
`
`
`
`
`
`
`metabolic acidosis for ketoacidosis regardless of blood glucose level. If
`
`
`suspected, discontinue QTERN, evaluate and treat promptly. Before
`
`initiating QTERN, consider risk factors for ketoacidosis. Patients on
`
`
`
`
`QTERN may require monitoring and temporary discontinuation of therapy
`
`
`
`in clinical situations known to predispose to ketoacidosis. (5.4, 6.2)
`
`Acute Kidney Injury and Impairment in Renal Function: Consider temporarily
`
`
`
`
`
`discontinuing in settings of reduced oral intake or fluid losses. If acute
`
`
`
`kidney injury occurs, discontinue and promptly treat. Monitor renal
`
`
`function during therapy. (5.5, 6.2)
`Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary
`
`
`
`
`
`
`tract infections and treat promptly, if indicated. (5.6, 6.2)
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin
`
`
`
`
`
`
`
`to reduce the risk of hypoglycemia when initiating QTERN. (5.7, 6.1)
`Hypersensitivity Reactions (e.g., urticaria, facial edema): There have been
`
`
`
`
`
`postmarketing reports of serious hypersensitivity reactions treated with
`
`
`saxagliptin, such as anaphylaxis, angioedema, and exfoliative skin
`
`
`conditions. Promptly discontinue QTERN, assess for other potential causes,
`
`
`
`institute appropriate monitoring and treatment, and initiate alternative
`
`
`treatment for diabetes. (5.8, 6.2)
`
`Genital Mycotic Infections: Monitor and treat if indicated. (5.9, 6.1)
`
`
`
`
`Increased LDL-C: Monitor and treat per standard of care. (5.10, 6.1)
`
`
`
`
`
`Bladder Cancer: An imbalance in bladder cancers was observed in clinical
`
`
`
`
`
`
`
`
`
`
`studies with dapagliflozin. QTERN should not be used in patients with
`
`
`
`
`active bladder cancer and should be used with caution in patients with a
`
`
`prior history of bladder cancer. (5.11)
`Arthralgia: Severe and disabling arthralgia has been reported in patients
`
`
`
`
`
`
`
`
`
`taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain
`
`and discontinue drug if appropriate. (5.12, 6.1, 6.2)
`Bullous Pemphigoid: There have been postmarketing reports of bullous
`
`
`
`
`pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors.
`
`Tell patients to report development of blisters or erosions. If bullous
`
`
`
`pemphigoid is suspected, discontinue QTERN. (5.13)
`Macrovascular Outcomes: There have been no clinical studies establishing
`
`
`
`
`
`conclusive evidence of macrovascular risk reduction with QTERN. (5.14)
`
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`
`
`Adverse reactions reported in ≥5% of subjects treated with 10 mg
`
`
`dapagliflozin and 5 mg saxagliptin were: upper respiratory tract infection,
`
`
`
`
`urinary tract infection, and dyslipidemia. (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 ----------------------------­
`Strong CYP3A4/5 Inhibitors (e.g., Ketoconazole): Do not coadminister
`
`
`
`
`
`QTERN with strong cytochrome P450 3A4/5 inhibitors. (2.3, 7.1)
`
`
`
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
`Pregnancy: Advise females of the potential risk to a fetus especially during
`
`
`
`
`
`the second and third trimesters. (8.1)
`Lactation: QTERN is not recommended when breastfeeding. (8.2)
`
`
`
`Geriatrics: Higher incidence of adverse reactions related to volume depletion
`
`
`
`
`
`
`and reduced renal function. (5.3, 5.5, 8.5)
`Renal Impairment: Higher incidence of adverse reactions related to reduced
`
`
`
`
`
`
`
`intravascular volume and renal function. (5.5, 6.1, 8.6)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`Revised: 02/2017
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage
`
`2.2 Patients with Renal Impairment
`
`
`2.3 Use with Strong CYP3A4/5 Inhibitors
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Pancreatitis
`
`5.2 Heart Failure
`
`5.3 Hypotension
`
`5.4 Ketoacidosis
`
`5.5 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`5.7 Hypoglycemia with Concomitant Use of Insulin or Insulin
`
`
`
`
`Secretagogues
`
`5.8 Hypersensitivity Reactions
`
`
`
`5.9 Genital Mycotic Infections
`
`
`
`
`5.10 Increases in Low-Density Lipoprotein Cholesterol (LDL–C)
`
`Reference ID: 4062027
`
`
`5.11 Bladder Cancer
`
`5.12 Severe and Disabling Arthralgia
`
`5.13 Bullous Pemphigoid
`
`5.14 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 Positive Urine Glucose Test
`
`
`7.3 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`8.6 Patients with Renal Impairment
`
`8.7 Patients with Hepatic 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 Add-on Therapy with Saxagliptin in Patients on Dapagliflozin plus
`
`
` Metformin
` 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.
`
`
`
`Reference ID: 4062027
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
` QTERN (dapagliflozin and saxagliptin) is indicated as an adjunct to diet and exercise to improve
`
`
`
` glycemic control in adults with type 2 diabetes mellitus (T2DM) who have inadequate control
` with dapagliflozin or who are already treated with dapagliflozin and saxagliptin [see Clinical
`
`
` Studies (14)].
`
`Limitations of Use
`
`
`
`
`QTERN is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`
`QTERN should only be used in patients who tolerate 10 mg dapagliflozin.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosage
`
`In patients with volume depletion, correct this condition prior to initiation of QTERN [see
`
`Warnings and Precautions (5.3), and Use in Specific Populations (8.5, 8.6)].
`
`
`
`The recommended dose of QTERN is a 10 mg dapagliflozin/5 mg saxagliptin tablet taken orally
`
`
`
`
`once daily in the morning with or without food.
`
`
`Do not split or cut QTERN tablets.
`
`
`2.2 Patients with Renal Impairment
`
`
`Assessment of renal function is recommended prior to initiation of QTERN therapy and
`
`periodically thereafter.
`
`
`Do not initiate QTERN in patients with an estimated glomerular filtration rate (eGFR) below
`
`60 mL/min/1.73 m2 .
`
`
`
`Discontinue QTERN if eGFR falls persistently below 60 mL/min/1.73 m2 [see Warnings and
`
`
` Precautions (5.5) and Use in Specific Populations (8.6)].
`
`
`
`QTERN is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see
`
`
`
`
`Contraindications (4)].
`
`
`
`2.3 Use with Strong CYP3A4/5 Inhibitors
`Do not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole,
`atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
`and telithromycin) [see Drug Interactions (7.1)].
`
`
`
`Reference ID: 4062027
`
`
`
`3 of 42
`
`

`

`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` QTERN tablets containing 10 mg dapagliflozin and 5 mg saxagliptin are light brown to brown,
`
`
`
` biconvex, round, film-coated, with “1122” printed on one side, in blue ink.
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
` QTERN is contraindicated in patients with:
`
` History of a serious hypersensitivity reaction to dapagliflozin or to saxagliptin, including
`
`
`
`
` anaphylaxis, angioedema or exfoliative skin conditions [see Warnings and Precautions
`
`
`
`
` (5.8) and Adverse Reactions (6.1)].
`
`
` Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end-stage
`
`
`
` renal disease (ESRD), or patients on dialysis [see Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`•
`
`
`
`
` •
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 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. Pre-existing 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 QTERN, observe patients for signs and symptoms of pancreatitis. If
`
`
`
`pancreatitis is suspected, promptly discontinue QTERN 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 QTERN.
`
`
`5.2 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.
`
`
`Reference ID: 4062027
`
`4 of 42
`
`
`
`

`

`Consider the risks and benefits of QTERN prior to initiating treatment in patients at a higher risk
`
`of 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 QTERN.
`
`
`5.3 Hypotension
`
`Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after
`
`initiating QTERN [see Adverse Reactions (6.1)] particularly in patients with impaired renal
`
`
`
`function (eGFR <60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics. Before
`
`
`
`
`initiating QTERN volume status should be assessed and corrected. Do not initiate QTERN in
`
`
`patients with an eGFR <60 mL/min/1.73 m2. Monitor for signs and symptoms of hypotension
`
`
`
`after initiating therapy.
`
`
`5.4 Ketoacidosis
`
`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have
`
`
`
`
`
`
`been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus
`
`
`
`
`
`
`
`
`
`
`receiving sodium glucose cotransporter-2 (SGLT-2) inhibitors, including dapagliflozin. Fatal
`
`
`
`
`
`cases of ketoacidosis have been reported in patients taking dapagliflozin. QTERN is not
`
`
`indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage
`
`
`
`
`
`
`
`
`
`
`
`
`(1)].
`
`Patients treated with QTERN who present with signs and symptoms consistent with severe
`
`
`
`
`
`
`metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose
`
`
`
`
`
`
`
`levels as ketoacidosis associated with QTERN may be present even if blood glucose levels are
`
`
`
`
`
`
`
`
`
`
`less than 250 mg/dL. If ketoacidosis is suspected, QTERN should be discontinued, the patient
`
`
`
`
`
`
`
`
`should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may
`
`
`
`require insulin, fluid and carbohydrate replacement.
`
`
`
`
`
`
`
`
`
`
` In many of the postmarketing reports for dapagliflozin, and particularly in patients with type 1
`
` diabetes, the presence of ketoacidosis was not immediately recognized and the institution of
`
`
`
`
`
`
` treatment was delayed because the presenting blood glucose levels were below those typically
`
`
`
`
`
`
` expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at
`
`
`
`
`
`
`
` presentation were consistent with dehydration and severe metabolic acidosis and included
`
`
`
`
`
`
`
`
`
` nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not
`
`
`
`
`
` all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness,
`
`
`
`
`
`
`
`
`
` reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin
`
`
`
`
`
`
`
` deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse
`
`
`
`
`
` were identified.
`
`
`
`
`
`
` Before initiating QTERN, consider factors in the patient history that may predispose to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction and
`
`
`
`Reference ID: 4062027
`
`5 of 42
`
`
`
`
`
`

`

`alcohol abuse. In patients treated with QTERN consider monitoring for ketoacidosis and
`
`
`
`
`
`
`temporarily discontinuing QTERN in clinical situations known to predispose to ketoacidosis
`
`
`
`
`
`
`
`(e.g., prolonged fasting due to acute illness or surgery) [see Adverse Reactions (6.2)] .
`
`
`
`
`
`
`
`
`5.5 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`Dapagliflozin causes intravascular volume contraction [see Warning and Precautions (5.3)], and
`
`
`
`can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing
`
`
`
`reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving
`
`
`
`dapagliflozin; some reports involved patients younger than 65 years of age.
`
`
`
`Before initiating QTERN, consider factors that may predispose patients to acute kidney injury
`
`
`
`including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant
`
`medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing
`
`QTERN in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses
`
`
`
`(gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of
`
`
`acute kidney injury. If acute kidney injury occurs, discontinue QTERN promptly and institute
`
`
`
`
`treatment.
`
`
`Dapagliflozin increases serum creatinine and decreases eGFR. Elderly patients and patients with
`
`impaired renal function may be more susceptible to these changes. Adverse reactions related to
`
`
`
`renal function can occur after initiating QTERN [see Adverse Reactions (6.1)]. Discontinue
`
`
`
`
`
`QTERN in patients if eGFR falls persistently below 60 mL/min/1.73 m2. QTERN is
`
`
`
`
`
`contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see Dosage and
`
`
`
`
`Administration (2.2), Contraindications (4), and Use in Specific Populations (8.6)].
`
`
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`
`
`
`
`
`
`
`There have been postmarketing reports of serious urinary tract infections including urosepsis and
`
`
`
`
`
`
`pyelonephritis requiring hospitalization in patients receiving SGLT-2 inhibitors, including
`
`
`
`
`
`
`
`
`
`
`
`dapagliflozin. Treatment with SGLT-2 inhibitors increases the risk for urinary tract infections.
`
`
`
`
`
`
`Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if
`
`
`indicated [see Adverse Reactions (6.2)].
`
`
`
`
`5.7 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues
`Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Both
`saxagliptin and dapagliflozin can individually increase the risk of hypoglycemia when combined
`with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin
`
`
`secretagogue may be required to reduce the risk of hypoglycemia when these agents are used in
`combination with QTERN [see Adverse Reactions (6.1)].
`
`
`Reference ID: 4062027
`
`6 of 42
`
`
`
`

`

`5.8 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 QTERN, treat per standard of care, and
`
`monitor until signs and symptoms are resolved. Assess for other potential causes for the event.
`
`
`Institute alternative treatment for diabetes.
`
`
`Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4)
`
`inhibitor because it is unknown whether such patients will be predisposed to angioedema with
`
` saxagliptin.
`
` 5.9 Genital Mycotic Infections
`
` Dapagliflozin increases the risks of genital mycotic infections. Patients with a history of genital
`
`
` mycotic infections were more likely to develop genital mycotic infections [see Adverse
`
`
` Reactions (6.1)]. Monitor and treat appropriately.
`
`
`
`
` 5.10 Increases in Low-Density Lipoprotein Cholesterol (LDL–C)
`
`
`
` Increases in LDL–C can occur with dapagliflozin [see Adverse Reactions (6.1)]. Monitor LDL-C
` and treat per standard of care after initiating QTERN.
`
`
`
`
` 5.11 Bladder Cancer
`
` Across 22 clinical studies for dapagliflozin, newly diagnosed cases of bladder cancer were
`
`
` reported in 10/6045 patients (0.17%) treated with dapagliflozin and 1/3512 patient (0.03%)
`
`
`
`
` treated with placebo/comparator. After excluding patients in whom exposure to study drug was
` less than one year at the time of diagnosis of bladder cancer, there were 4 cases with
`
`
`
` dapagliflozin and no cases with placebo/comparator. Bladder cancer risk factors and hematuria
` (a potential indicator of pre-existing tumors) were balanced between treatment arms at baseline.
`
`
`
`
` There were too few cases to determine whether the emergence of these events is related to
`
` dapagliflozin.
`
`
`
`
`
` There are insufficient data to determine whether dapagliflozin has an effect on pre-existing
`
`bladder tumors. Consequently, QTERN should not be used in patients with active bladder cancer.
`
` In patients with prior history of bladder cancer, the benefits of glycemic control versus unknown
` risks for cancer recurrence with QTERN should be considered.
`
`
`
` 5.12 Severe and Disabling Arthralgia
`
` There have been postmarketing reports of severe and disabling arthralgia in patients taking
`
`
`DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied
`
`
`from one day to years. Patients experienced relief of symptoms upon discontinuation of the
`
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`
`

`

` medication. A subset of patients experienced a recurrence of symptoms restarting the same drug
`
`
`or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain
`
`and discontinue drug if appropriate [see Adverse Reactions (6)].
`
`
`
`
`5.13 Bullous Pemphigoid
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with
`
`DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic
`
`immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report
`development of blisters or erosions while receiving QTERN. If bullous pemphigoid is suspected,
`
`
`
`QTERN should be discontinued and referral to a dermatologist should be considered for
`
`diagnosis and appropriate treatment.
`
`
`5.14 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`
`reduction with QTERN.
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`The following important adverse reactions are described below or elsewhere in the labeling:
`
`
`• Pancreatitis [see Warnings and Precautions (5.1)]
`
`
`
`• Heart Failure [see Warnings and Precautions (5.2)]
`
`
`
`• Hypotension [see Warnings and Precautions (5.3)]
`
`
`
`• Ketoacidosis [see Warnings and Precautions (5.4)]
`
`
`
`• Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions
`
`
`
`(5.5)]
`
`
`• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)]
`
`
`• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see Warnings and
`
`
`
`
`
`Precautions (5.7)]
`
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.8)]
`
`
`
`
`• Genital Mycotic Infections [see Warnings and Precautions (5.9)]
`
`
`
`
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions
`
`
`
`•
`
`(5.10)]
`
`• Bladder Cancer [see Warnings and Precautions (5.11)]
`
`
`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
`
`
`
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`

`
`
` • Bullous Pemphigoid [see Warnings and Precautions (5.13)]
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
` The safety of combined use of 10 mg dapagliflozin and 5 mg saxagliptin has been evaluated in
` 492 adult subjects with type 2 diabetes in a pooled safety analysis of three phase 3
`
`
`
`
`
`
`
` active/placebo-controlled clinical trials with a median exposure of 51 weeks. The mean age of
` these subjects was 54 years, 0.8% were 75 years or older and 53.7% were female. The population
`
` was 80.9% White, 8.3% Black or African American, 3.7% Asian, and 6.6% Other race. At
`
`
`
`
` baseline the population had diabetes for an average of 7.5 years and a mean HbA1c of 8.4%. The
`
`
` mean eGFR at baseline was 94.4 mL/min/1.73 m2 .
`
`
`
`
`
`
`
`The common adverse reactions were based on the pooled analyses of these studies as shown in
`
`
`Table 1.
`
`
`
`Table 1. Adverse Reactions Reported in ≥2% Subjects Treated with 10 mg Dapagliflozin
`
`
`
`
`and 5 mg Saxagliptin
`
`
`
`
` Adverse Reaction
`
` Preferred Term*
`
`
`
` QTERN
`
` Frequency
`
`
` %
` Upper respiratory tract infection*
`
` 13.6
` Urinary tract infection*
`
`
` 5.7
`
` Dyslipidemia*
`
` 5.1
`
`Headache
`
` 4.3
`
`Diarrhea
`
` 3.7
`
`Back pain
`
` 3.3
`
`Genital infection*
`
` 3.0
`
`Arthralgia
`
` 2.4
` * Adverse reactions that are medically related were grouped to a single preferred term.
`
`
` Additionally, adverse reactions reported in <5% and ≥2% from the dapagliflozin development
`
`program and ≥1% more frequently compared to placebo included increased urination, and
`
`discomfort with urination.
`
`Hypoglycemia
`
`
`
`
`
`
`
`Hypoglycemia was reported in 8 subjects (1.6%) treated with QTERN. No episodes of major
`
`
`
`hypoglycemia (defined as a symptomatic episode requiring external assistance) were reported.
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`Reference ID: 4062027
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`

`
`
` Genital Mycotic Infections
`
`
`
`
` Genital mycotic infections were reported in 15 subjects (3%) treated with QTERN. Reported
` adverse reactions by frequency included vulvovaginal mycotic infection, balanoposthitis, genital
`
`
` fungal infection, vaginal infection, and vulvovaginitis. The majority of subjects (84.2%) who
`
`
`
`
`
` experienced genital infection adverse reactions were females.
`
`
`
`
`
` Urinary Tract Infections
`
`
`
` Urinary tract infections were reported in 28 subjects (5.7%) treated with QTERN. Reported
` adverse reactions by frequency included urinary tract infection, Escherichia urinary tract
`
`
` infection, prostatitis, and pyelonephritis. The majority of subjects (80.6%) who experienced
`
`
`
` urinary tract infection adverse reactions were females.
`
`
`
` Volume Depletion
`
`Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reported
`
`in 2 subjects (0.4%) treated with QTERN.
`
`
`
`Renal Impairment
`
`
`
`Adverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated
`
`with QTERN. The reported adverse reactions included decreased glomerular filtration rate, renal
`
`
`
`impairment, increased blood creatinine, acute renal failure, and decreased urine output. None of
`
`
`
`the adverse reactions was reported as serious and all but one were mild to moderate in intensity.
`Three subjects discontinued due to decreased eGFR. Subjects with AEs of renal impairment had
`
`lower mean eGFR values at baseline of 64.4 ml/min/1.73 m2 compared to 94.4 ml/min/1.73 m2
`
`
`
`
`
`
`
`
`
`in overall population treated with QTERN.
`
`
`Dapagliflozin
`
`
`
`Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR
`(see Table 2). In patients with normal or mildly impaired renal function at baseline, serum
`creatinine and eGFR returned to baseline values at Week 24. Sustained decreases in eGFR were
`seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2).
`
`
`
`
`
`Elderly patients and patients with impaired renal function were more susceptible to these adverse
`
`reactions.
`
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`
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`

`
`
` Table 2. Changes in Serum Creatinine and eGFR Associated with Dapagliflozin
`
`
`
`
`
`
`
`
`
`
`
` Baseline Mean
`
`
`
` Week 1 Change
`
`
`
`
` Serum Creatinine (mg/dL)
`
` eGFR (mL/min/1.73 m2)
`
` Serum Creatinine (mg/dL)
`
` eGFR (mL/min/1.73 m2)
` Week 24 Change Serum Creatinine (mg/dL)
`
`
` eGFR (mL/min/1.73 m2)
`
`
`
`
`
`
`
`
` Baseline Mean
`
`
`
` Week 1 Change
`
`
` Serum Creatinine (mg/dL)
`
` eGFR (mL/min/1.73 m2)
`
` Serum Creatinine (mg/dL)
`
` eGFR (mL/min/1.73 m2)
` Week 24 Change Serum Creatinine (mg/dL)
`
`
` eGFR (mL/min/1.73 m2)
` Week 52 Change Serum Creatinine (mg/dL)
`
`
` eGFR (mL/min/1.73 m2)
`
`
`
`
`
`
` Pool of 12 Placebo-Controlled Studies
`
` Dapagliflozin 10 mg
`
` Placebo
`
` Dapagliflozin 5 mg
`
`
` N=1393
`
`
` N=1193
` N=1145
` 0.860
`
`
`
` 0.853
` 0.847
` 86.0
` 85.3
` 86.7
`
`
`
`
` −0.003
` 0.029
` 0.041
`
`
`
` −2.9
`
` −4.1
`
` 0.4
`
` −0.005
` −0.001
`
` 0.001
`
`
`
`
` 0.3
` 0.8
` 0.8
`
` Moderate Renal Impairment Study
`
`
`
` Dapagliflozin 5 mg
` Dapagliflozin 10 mg
`
` Placebo
`
` N=83
`
`
`
` N=84
` N=85
`
`
`
` 1.46
` 1.53
` 1.52
`
` 45.6
`
` 44.2
`
` 43.9
`
` 0.01
`
` 0.13
`
` 0.18
`
` −3.8
`
` −5.5
`
` 0.5
`
` 0.02
`
` 0.08
`
` 0.16
`
` 0.03
`
` −4.0
`
` −7.4
`
` 0.10
`
` 0.06
`
` 0.15
`
` −2.6
`
` −4.2
`
` −7.3
`
`
` Laboratory Findings
`
`
`
`Decrease in Lymphocyte Counts
`
`
`Saxagliptin
`
`
`A dose-related mean decrease in absolute lymphocyte count has been observed with saxagliptin.
`
`In a pool of 5 placebo-controlled studies, a mean decrease in absolute lymphocyte count of
`
`
`approximately 100 cells/microL relative to placebo. There was a dose-related mean decrease in
`
`
`
`
`absolute lymphocyte count observed with saxagliptin. The proportion of patients who were
`
`
`reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, and 0.4% in the
`
`saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. The decreases in lymphocyte count
`
`
`were not associated with clinically relevant adverse reactions.
`
`
`
`
`The clinical significance of this decrease in lymphocyte count relative to placebo is not known.
`
`When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte
`
`count should be measured. The effect of saxagliptin on lymphocyte counts in patients with
`
`lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
`
`
`
`
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`

`Increase in Hematocrit
`
`
`
`Dapagliflozin
`
`
`
`
`In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean
`
`
`
`
`hematocrit values were observed in dapagliflozin treated patients starting at Week 1 and
`
`
`continuing up to Week 16, when the maximum mean difference from baseline was observed. At
`
`
`Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and
`
`
`
`
`2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in
`
`
`
`
`0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients.
`
`Increase in Serum Inorganic Phosphorus
`
`
`Dapagliflozin
`
`
`
`
`
`
`In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean
`
`
`
`serum phosphorus levels were reported at Week 24 in dapagliflozin treated patients compared
`
`with placebo-treated patients (mean increase of 0.13 versus −0.04 mg/dL, respectively). Higher
`
`
`proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL
`
`
`
`
`for age 17-65 years or ≥5.1 mg/dL for age ≥66 years) were reported on dapagliflozin at Week 24
`
`
`(0.9% versus 1.7% for placebo and dapagliflozin 10 mg, respectively).
`
`
`
` Increase in Low-Density Lipoprotein Cholesterol
`
`
`
`
`
` Patients treated with QTERN demonstrated a mean percent increase from baseline
`
` LDL-cholesterol (ranging from 2.1 to 6.9%).
`
`
`
`
`
` Elevations in Creatine Kinase
`
`
`
` In the pooled safety analysis, an imbalanc