`
`
`
` 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
`
`
`
`
`
`-------------------------- RECENT MAJOR CHANGES -------------------------­
`
`
`
`
`
`
`Indications and Usage (1)
`5/2019
`
`
`
`
`Dosage and Administration (2.1, 2.2, 2.3)
`5/2019
`
`
`
`
`
`10/2018
`Warning and Precautions (5.8)
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`QTERN is a sodium-glucose cotransporter 2 (SGLT2) 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. (1)
`
`
`Limitations of Use:
`
`QTERN is not indicated for the treatment of type 1 diabetes mellitus or
`
`
`
`
`
`diabetic ketoacidosis. (1)
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`• Assess renal function before initiation of therapy and periodically
`
`
`
`thereafter. (2.1)
`
`• Take QTERN orally, once daily in the morning with or without food. (2.2)
`
`
`
`
`• For patients not already taking dapagliflozin, the recommended starting
`
`
`dose of QTERN is a 5 mg dapagliflozin/5 mg saxagliptin tablet once daily.
`
`
`
`
`
`
`
`(2.2)
`
`• In patients tolerating 5 mg dapagliflozin and 5 mg saxagliptin once daily
`
`
`
`
`
`who require additional glycemic control, the QTERN dose can be increased
`
`to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily. (2.2)
`
`
`
`
`
`
`
`• Do not coadminister QTERN with strong cytochrome P450 3A4/5
`
`
`
`
`inhibitors. (2.4, 7)
`
`• Swallow tablet whole. Do not crush, cut or chew. (2.2)
`
`
`
`
`
`
`
`
`
`---------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`• Tablet: 5 mg dapagliflozin/5 mg saxagliptin (3)
`
`
`
`
`• 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
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Prior to Initiation of QTERN
`
`2.2 Dosage
`
`
` 2.3 Patients with Renal Impairment
`
`2.4 Use with Strong CYP3A4/5 Inhibitors
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pancreatitis
`
`
`
`Reference ID: 4456142
`
`
`
`
`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)
`
`
`
`Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-
`
`
`
`
`threatening cases have occurred in both females and males. Assess patients
`
`
`
`presenting with pain or tenderness, erythema, or swelling in the genital or
`
`
`perineal area, along with fever or malaise. If suspected, institute prompt
`
`treatment. (5.8)
`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. (5.9, 6.2)
`
`Genital Mycotic Infections: Monitor and treat if indicated. (5.10, 6.1)
`
`
`
`
`
`Increased LDL-C: Monitor and treat per standard of care. (5.11, 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. (5.12)
`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. (5.13, 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. (5.14)
`Macrovascular Outcomes: There have been no clinical studies establishing
`
`
`
`
`conclusive evidence of macrovascular risk reduction with QTERN. (5.15)
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`
`
`
`Adverse reactions reported in ≥5% of subjects treated with dapagliflozin and
`
`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)
`
`
`
`
`
`
`
`
`
`
`
`----------------------- 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: 6/2019
`
`
`
`
`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 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`
`
`5.9 Hypersensitivity Reactions
`
`5.10 Genital Mycotic Infections
`
`
`
` 1
`
`

`

`
`
`
`
`
` 5.11 Increases in Low-Density Lipoprotein Cholesterol (LDL–C)
`
`
`
`5.12 Bladder Cancer
`
`
`5.13 Severe and Disabling Arthralgia
`
`
`5.14 Bullous Pemphigoid
`
`
`5.15 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`
`8.7 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 Dapagliflozin plus Saxagliptin in Patients on
`
`
`
`
`
`
`Metformin
`
`14.2 Add-on Therapy with Saxagliptin in Patients on Dapagliflozin plus
`
`
`
`
`Metformin
`
`
`14.3 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: 4456142
`
`
`
` 2
`
`

`

`
`
` 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.
`
`
`
`
`
`
`
`
`
`Limitations of Use
`
`
`
`QTERN is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` 2.1 Prior to Initiation of QTERN
` Assess renal function prior to initiation of QTERN therapy and periodically thereafter [see WARNINGS
`
`
`AND PRECAUTIONS (5.5)].
`
`
`
`
`
`
`
`
`
`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)].
`
`
`
`
` 2.2 Dosage
`
`
` For patients not already taking dapagliflozin, the recommended starting dose of QTERN is a 5 mg
`
`
`
`
`dapagliflozin/5 mg saxagliptin tablet taken orally once daily in the morning with or without food.
`
`
`
`
`
`
`
`
`In patients tolerating 5 mg dapagliflozin and 5 mg saxagliptin once daily who require additional glycemic
`
`
`
`
`
`control, the QTERN dose can be increased to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily in
`
`
`
`
`
`
`the morning with or without food.
`
`
`Swallow whole. Do not crush, cut or chew QTERN tablets.
`
`
`
`
`
` 2.3 Patients with Renal Impairment
`
`
`
` No dose adjustment is needed in patients with an estimated glomerular filtration rate (eGFR) greater than
`
`
` or equal to 45 mL/min/1.73 m2.
`
`
`
`
`
`
` QTERN is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see
`
`
`
`
`CONTRAINDICATIONS (4) and USE IN SPECIFIC POPULATIONS (8.6)].
`
`
`
`
`
`
`
`
`
`
` 2.4 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)].
`
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 3
`
`

`

`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` Tablets:
`
` • 5 mg dapagliflozin/5 mg saxagliptin as light purple to reddish purple, biconvex, round, film-coated
`
`
`
`
`
`
` tablet, with “1120” printed on both sides, in blue ink.
`
`
`
` • 10 mg dapagliflozin/5 mg saxagliptin as light brown to brown, biconvex, round, film-coated tablet,
`
`
`
`
`
`
` with “1122” printed on both sides, 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: 4456142
`
`
`
` 4
`
`

`

`
`
`
`
`
`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. QTERN is contraindicated in patients with an
`
`
`
`
`eGFR <45 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 (SGLT2) 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 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)].
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 5
`
`

`

` 5.5 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`
` Dapagliflozin causes intravascular volume contraction [see WARNINGS 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, and 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)]. Renal function should be evaluated
`
`
`
`
`
`
`prior to initiation of QTERN and monitored periodically thereafter. 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 SGLT2 inhibitors, including dapagliflozin.
`
`
`
`
`
`
` Treatment with SGLT2 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
`
`
`
`
` dapagliflozin and saxagliptin 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)].
`
`
`
`
`
`
`
`
` 5.8 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
` Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-
`
`
`
`threatening necrotizing infection requiring urgent surgical intervention, have been identified in
`
`
`
`postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including
`
`
`
`dapagliflozin. Cases have been reported in females and males. Serious outcomes have included
`
`
`hospitalization, multiple surgeries, and death.
`
`
`Patients treated with QTERN presenting with pain or tenderness, erythema, or swelling in the genital or
`
`
`
`perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start
`
`
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 6
`
`

`

` treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement.
`
`
`Discontinue QTERN, closely monitor blood glucose levels, and provide appropriate alternative therapy
`
`
`
`for glycemic control.
`
`
` 5.9 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.
`
`
`
`
`
`
`
`
` 5.10 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.
`
` 5.11 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.
`
`
`
`
`
`
`
`
`
` 5.12 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.
`
`
` 5.13 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 medication. A subset of
`
`
` patients experienced a recurrence of symptoms restarting the same drug or a different DPP-4 inhibitor.
`
`
`
`
`Reference ID: 4456142
`
`
`
` 7
`
`

`

`Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate
`
`
`
`
`
`[see ADVERSE REACTIONS (6)].
`
`
` 5.14 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.
`
`
` 5.15 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)]
`
`
`
`
`
`
`
` • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see WARNINGS AND PRECAUTIONS
`
`
` (5.8)]
`
`
`
` • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.9)]
`
`
`
`
` • Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS (5.10)]
`
`
`
`•
`
`
` Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see WARNINGS AND PRECAUTIONS
`
` (5.11)]
`
`
`
`
`
`
`
` • Bladder Cancer [see WARNINGS AND PRECAUTIONS (5.12)]
`
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 8
`
`

`

`
`
` • Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS (5.13)]
`
`
`
`
` • Bullous Pemphigoid [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.
`
`
`
` The safety of combined use of 10 mg dapagliflozin and 5 mg saxagliptin has been evaluated in 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 pooled safety analysis included a total of 1169 adults:
`
`
`
`
`
`
` 492 patients in the combination of saxagliptin and dapagliflozin plus metformin group, 341 patients in the
`
`
`
`
`
`
`
`
`
`
` dapagliflozin plus metformin group, 336 patients in the saxagliptin plus metformin group. 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.
`
`
`
`
`
` Frequency %
`
`
`
`
`
`
`
`
`
`
`
` Table 1: Adverse Reactions Reported in ≥2% of Subjects
`
` Treated with 10 mg Dapagliflozin and 5 mg Saxagliptin plus
`
`
`
` Metformin (≥1500 mg)
`
`
`
` Adverse Reaction
`
` Preferred Term*
`
` 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.
`
`
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 9
`
`

`

`
`
` Hypoglycemia
`
`In the pooled analysis, the incidences of hypoglycemia (defined as a blood glucose <54 mg/dL regardless
`
`
`
`
`
`of the presence or absence of symptoms) and severe hypoglycemia (event requiring assistance due to
`
`
`
`neuroglycopenia, characterized by altered mental and/or physical status) was 1% and 0.2%, respectively.
`
`
`
`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
`
`
`
`Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Events
`
`related to volume depletion (hypotension, dehydration, and hypovolemia) were reported in 2 subjects
`
`(0.4%) treated with QTERN plus metformin.
`
`
`
`
`Impairment of Renal Function
`
`
`
`Adverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated with
`
`
`
`
`QTERN plus metformin. 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 were 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. Renal-related adverse reactions, including renal failure and
`
`
`
`blood creatinine increase, were more frequent in patients treated with dapagliflozin (see Table 3). Elderly
`
`
`
`
`
`
`patients and patients with impaired renal function were more susceptible to these adverse reactions (see
`Table 3). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to
`
`
`
`
`less than 60 mL/min/1.73 m2). QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m2.
`
`
`
`
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 10
`
`

`

`
`
`
` Table 2: Changes in Serum Creatinine and eGFR Associated with Dapagliflozin in the
`Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Studies
`
`
` Pool of 12 Placebo-Controlled Studies
`
`
` 10 mg Dapagliflozin
`
` Placebo
`
`
` 5 mg
`
`
`
`
` N=1393
` Dapagliflozin
`
` N=1193
`
` N=1145
`
` 0.860
`
`
`
`
`
`
`
` 0.853
`
`
`
` 0.847
`
`
`
` 86.0
`
`
`
` −0.003
`
`
`
` 0.4
`
`
`
` 85.3
`
`
`
` 0.029
`
`
`
` −2.9
`
`
`
` −0.005
`
`
`
` −0.001
`
`
`
` 0.8
`
`
`
` 0.8
`
`
`
` 86.7
`
`
`
` 0.041
`
`
`
` −4.1
`
`
`
` 0.001
`
`
`
` 0.3
`
`
`
` Moderate Renal Impairment Study*
`
` (eGFR 30 to less than 60 mL/min/1.73 m2)
`
`
`
` 10 mg Dapagliflozin
`
` Placebo
`
`
` 5 mg
`
` Dapagliflozin
`
` N=84
` N=85
`
` N=83
`
` 1.53
`
`
`
`
`
`
`
` 1.46
`
`
`
` 1.52
`
`
`
` Baseline Mea