`
`
`
`
`
` 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
`
` 1/2020
`
`
`
` Warnings and Precautions (5.4, 5.5)
` Warnings and Precautions (5.11, 5.12)
`
` Removed 1/2020
`
`
`
`
`
`
`
`--------------------------- 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
`
`
`
`QTERN may require monitoring and temporary discontinuation of therapy
`
`
`
`in clinical situations known to predispose to ketoacidosis. (5.4, 6.2)
`
`
`Acute Kidney Injury: 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)
`
`
`
`
`
`
`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. (5.11, 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. (5.12)
`
`
`Macrovascular Outcomes: There have been no clinical studies establishing
`
`
`conclusive evidence of macrovascular risk reduction with QTERN. (5.13)
`
`
`
`
`
`------------------------------ 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, 8.6)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`Revised: 1/2020
`
`
`
`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
`
`5.2 Heart Failure
`
`5.3 Hypotension
`
`
`
`Reference ID: 4551346
`
`
`5.4 Ketoacidosis
`
`5.5 Acute Kidney Injury
`
`
`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
`
`5.11 Severe and Disabling Arthralgia
`
`5.12 Bullous Pemphigoid
`
`5.13 Macrovascular Outcomes
`
`6 ADVERSE REACTIONS
`
`
`
` 1
`
`

`

`
` 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: 4551346
`
`
`
` 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: 4551346
`
`
`
` 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 anaphylactic
`
`
`
`
`
` reactions, angioedema or exfoliative skin conditions [see WARNINGS AND PRECAUTIONS (5.9)
`
`
`
` 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: 4551346
`
`
`
` 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 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, 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.
`
`
`
`
`
`
`
`
`
`
`
`For patients who undergo elective surgery, consider temporarily discontinuing QTERN for at least 3 days prior
`
`
`
`to surgery [see Clinical Pharmacology (12.2, 12.3)].
`
`
`
`
`Reference ID: 4551346
`
`
`
` 5
`
`

`

`
`
`
`
`
`
`
`
` Consider monitoring for ketoacidosis and temporarily discontinuing QTERN in other clinical situations
`known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery) [see
`
`
`
`
`
`
`
`ADVERSE REACTIONS (6.2)]. Ensure risk factors for ketoacidosis are resolved prior to restarting
`
`
`
`QTERN.
`
`
`
`
`Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue QTERN
`
`
`
`
`
`
`and seek medical attention immediately if signs and symptoms occur.
`
`
`
`
` 5.5 Acute Kidney Injury
`
`
` Dapagliflozin causes intravascular volume contraction [see WARNINGS AND PRECAUTIONS (5.3)], and
`
`
`can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some
`
`
`
`
`requiring hospitalization and dialysis, in patients receiving dapagliflozin.
`
`
`
`
`Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of
`
`
`QTERN. Elderly patients and patients with impaired renal function may be more susceptible to these
`
`
`
`changes. 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 the setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as
`
`
`
`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.
`
`
`
`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 (2.3), 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
`
`
`
`
`
`
`Reference ID: 4551346
`
`
`
` 6
`
`

`

`
`
`
`postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including
`
`
`
`
`dapagliflozin. Cases have been reported in both 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
`
`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 anaphylactic reactions, 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 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.
`
`
`
` Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate
`
`
` [see ADVERSE REACTIONS (6)].
`
` 5.12 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.
`
`
`
`
`
`
`
`Reference ID: 4551346
`
`
`
` 7
`
`

`

` 5.13 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 [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)]
`
`
`
` • Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS (5.11)]
`
`
`
` • Bullous Pemphigoid [see WARNINGS AND PRECAUTIONS (5.12)]
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`Reference ID: 4551346
`
`
`
` 8
`
`

`

`
`
`
`
` 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.
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`Reference ID: 4551346
`
`
`
` 9
`
`

`

`
`
` 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.
`
`
`Ketoacidosis
`
`
`
`Dapagliflozin
`
`In the cardiovascular outcome study with dapagliflozin in patients with type 2 diabetes mellitus, events of
`
`
`
`
`
`
`
`diabetic ketoacidosis were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12
`
`out of 8569 patients in the placebo group. The events were evenly distributed over the study period.
`
`
`
`
`
`
`Laboratory Findings
`
`
`Increases in Serum Creatinine and Decreases in eGFR
`
`
`Dapagliflozin
`
`
`Initiation of dapagliflozin causes an increase in serum creatinine and decrease in eGFR. In patients with
`
`
`
`normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline 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) [see WARNINGS AND PRECAUTIONS (5.5) and MECHANISM OF
`
`
`
`
`
`ACTION (12.1)].
`
`
`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 was observed. 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 2.5 mg, 5 mg saxagliptin and
`
`placebo groups, respectively.
`
`
`
`
`
`The clinical significance of this decrease in lymphocyte count relative to placebo is not known. The effect
`of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human
`
`immunodeficiency virus) is unknown.
`
`
`
`Reference ID: 4551346
`
`
`
` 10
`
`

`

`
`
` 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 10 mg dapagliflozin group. By
`
`
`
`
`
`Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of 10 mg
`
`
`
`
`
`dapagliflozin-treated patients.
`
`
`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
`
`
`
`An imbalance in the number of subjects who experienced serum creatine kinase (CK) elevations >10x the
`
`
`
`
`upper limit of normal (a marker of muscle injury/necrosis) was observed in 5 subjects (1%) treated with
`
`
`
`
`QTERN. The elevations were transient. Rhabdomyolysis was reported for one of those subjects for which
`
`
`
`no obvious cause was identified.
`
`
`
`
`
`Decrease in Serum Bicarbonate
`
`
`In a study of concomitant therapy of 10 mg dapagliflozin with exenatide extended-release (on a
`
`
`
`
`
`background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of
`
`
`
`
`
`
`less than or equal to 13 mEq/L compared to one each (0.4%) in t