HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` QTERNMET XR safely and effectively. See full prescribing information
`
`
`
` for QTERNMET XR.
`
`
`
` QTERNMET® XR (dapagliflozin, saxagliptin, and metformin
`
` hydrochloride) extended-release tablets, for oral use
`
`
` Initial U.S. Approval: 2019
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
` WARNING: LACTIC ACIDOSIS
`
`
`
` See full prescribing information for complete boxed warning.
`
` Postmarketing cases of metformin-associated lactic acidosis
`
`
`
` have resulted in death, hypothermia, hypotension, and resistant
`bradyarrhythmias. Symptoms included malaise, myalgias,
`respiratory distress, somnolence, and abdominal pain.
`Laboratory abnormalities included elevated blood lactate
`
`
`
`levels, anion gap acidosis, increased lactate/pyruvate ratio; and
`
`
`
`
`
`
`
`
`metformin plasma levels generally >5 mcg/mL. (5.1)
`
`Risk factors include renal impairment, concomitant use of
`
`
`
`
`certain drugs, age >65 years old, radiological studies with
`
`
`contrast, surgery and other procedures, hypoxic states,
`
`
`excessive alcohol intake, and hepatic impairment. Steps to
`
`
`reduce the risk of and manage metformin-associated lactic
`
`
`acidosis in these high-risk groups are provided in the Full
`
`Prescribing Information. (5.1)
`
`If lactic acidosis is suspected, discontinue QTERNMET XR and
`
`
`institute general supportive measures in a hospital setting.
`
` Prompt hemodialysis is recommended. (5.1)
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`
`
`
`
`
`Lactic acidosis: See boxed warning (2.2, 4, 5.1)
`
`Pancreatitis: If pancreatitis is suspected, promptly discontinue. (5.2, 6.2)
`
`
`
`
`Heart Failure: Consider the risks and benefits of QTERNMET XR in patients
`
`
`
`
`
`who have known risk factors for heart failure. Monitor patients. (5.3)
`
`
`Hypotension: Before initiating QTERNMET XR, 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. (5.4, 6.1)
`
`
`
`
`Ketoacidosis: Assess patients who present with signs and symptoms of
`
`
`
`metabolic acidosis for ketoacidosis regardless of blood glucose level. If
`
`
`
`suspected, discontinue QTERNMET XR, evaluate and treat promptly.
`
`
`Before initiating QTERNMET XR, consider risk factors for ketoacidosis.
`
`
`Patients on QTERNMET XR may require monitoring and temporary
`
`discontinuation of therapy in clinical situations known to predispose to
`
`
`
`
`ketoacidosis. (5.5, 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. (5.6, 6.2)
`
`
`Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary
`
`
`
`
`tract infections and treat promptly, if indicated. (5.7, 6.2)
`
`
`
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin
`
`
`to reduce the risk of hypoglycemia when initiating QTERNMET XR in
`
`
`
`
`combination with these agents. (5.8, 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. (5.9)
`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 QTERNMET XR, assess for other
`
`
`potential causes, institute appropriate monitoring and treatment, and initiate
`
`
`
`
`alternative treatment for diabetes. (5.10, 6.2)
`
`
`
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Measure
`
`
`
`
`hematological parameters annually. (5.11, 6.1)
`
`Genital Mycotic Infections: Monitor and treat if indicated. (5.12, 6.1)
`
`
`
`
`
`Increased LDL-C: Monitor and treat per standard of care. (5.13, 6.1)
`
`
`
`
`
`Bladder Cancer: An imbalance in bladder cancers was observed in clinical
`
`
`
`
`
`
`
`
`
`
`studies with dapagliflozin. QTERNMET XR 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. (5.14)
`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. (5.15, 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 QTERNMET XR. (5.16)
`Macrovascular Outcomes: There have been no clinical studies establishing
`
`
`
`conclusive evidence of macrovascular risk reduction with QTERNMET
`
`XR. (5.17)
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`Adverse reactions reported in ≥5% of subjects treated with dapagliflozin and
`
`
`
`
`
`saxagliptin plus metformin 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
`
`
`
`QTERNMET XR with strong cytochrome P450 3A4/5 inhibitors. (2.4, 7)
`
`
`
`
`Carbonic anhydrase inhibitors: May increase the risk of lactic acidosis.
`Consider more frequent monitoring. (7)
`
`
`Drugs that reduce metformin clearance (such as ranolazine, vandetanib,
`
`
`
`
`dolutegravir, and cimetidine): May increase the accumulation of
`
`
`
`metformin. Consider the benefits and risks of concomitant use. (7)
`
`
`
`
`
`Alcohol: Can potentiate the effect of metformin on lactate metabolism. Warn
`
`
`
`patients against excessive alcohol intake. (7)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` --------------------------- INDICATIONS AND USAGE -------------------------­
` QTERNMET XR is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a
`
`
`
` dipeptidyl peptidase-4 (DPP-4) inhibitor and a biguanide 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
`
`• Is not indicated for the treatment of type 1 diabetes mellitus or diabetic
`
`
`
`
`
`
`ketoacidosis. (1)
`
`• QTERNMET XR initiation is intended only for patients currently taking
`
`
`
`
`metformin. (1)
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`• Assess renal function before initiation of therapy and periodically
`
`
`
`thereafter. (2.1)
`
`
`• Individualize the starting total daily dose of QTERNMET XR based on the
`
`
`
`patient’s current regimen, effectiveness, and tolerability. (2.2)
`
`• Take QTERNMET XR orally, once daily in the morning with food. (2.2)
`
`
`
`• For patients not currently taking dapagliflozin, the recommended starting
`
`
`
`total daily dose of QTERNMET XR is a 5 mg dapagliflozin/5 mg
`
`
`saxagliptin/1000 mg or 2000 mg metformin hydrochloride (HCl) once
`
`
`
`
`
`
`daily. (2.2)
`
`• The maximum recommended daily dose is 10 mg dapagliflozin, 5 mg
`
`
`
`
`
`
`saxagliptin and 2000 mg metformin HCl. (2.2)
`
`• Swallow tablet whole. Do not crush, cut or chew. (2.2)
`
`
`
`
`
`
`• Discontinue QTERNMET XR at the time of, or prior to, an iodinated
`
`
`
`
`
`
`contrast imaging procedure. (2.5)
`
`
`---------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`• Tablet: 2.5 mg dapagliflozin/2.5 mg saxagliptin/1000 mg metformin HCl
`
`
`
`
`
`extended-release (3)
`
`• Tablet: 5 mg dapagliflozin/2.5 mg saxagliptin/1000 mg metformin HCl
`
`
`
`
`
`
`extended-release (3)
`
`• Tablet: 5 mg dapagliflozin/5 mg saxagliptin/1000 mg metformin HCl
`
`
`
`
`
`
`extended-release (3)
`
`• Tablet: 10 mg dapagliflozin/5 mg saxagliptin/1000 mg metformin HCl
`
`
`
`
`
`
`extended-release (3)
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`
`
`
`
`• History of a serious hypersensitivity reaction to dapagliflozin, saxagliptin,
`
`
`
`
`or metformin, including anaphylaxis, angioedema, or exfoliative skin
`
`
`conditions. (4, 5.9, 6.2)
`
`
`• Moderate to severe renal impairment (eGFR <45 mL/min/1.73 m2),
`
`
`
`
`
`
`
`
`
`
`end-stage renal disease (ESRD), or patients on dialysis. (4)
`
`
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with
`
`
`
`
`
`
`
`or without coma. Diabetic ketoacidosis should be treated with insulin. (4)
`
`
`
`
`
`Reference ID: 4456142
`
`
`
` 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: QTERNMET XR is not recommended when breastfeeding. (8.2)
`
`
`
`
`Females and Males of Reproductive Potential: Advise premenopausal females
`
`
`
`
`
`of the potential for an unintended pregnancy. (8.3)
`
`
`Geriatrics: Higher incidence of adverse reactions related to volume depletion
`
`
`
`and reduced renal function. (5.4, 5.6, 8.5)
`
`
`
`
`
`
`Renal Impairment: Higher incidence of adverse reactions related to reduced
`
`
`
`intravascular volume and renal function. (2.2, 5.6, 6.1, 8.6)
`
`
`
`
`Hepatic Impairment: Avoid use of QTERNMET XR in patients with clinical
`
`
`
`
`
`or laboratory evidence of hepatic impairment. (2.3, 8.7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide
`
`
`Revised: 6/2019
`
`
`
`
`7
`
`8
`
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`DESCRIPTION
`11
`
`
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`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
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`
`
`13
`
`
`14
`
`
`3
`
`4
`
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: LACTIC ACIDOSIS
`
`
`INDICATIONS AND USAGE
`1
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Prior to Initiation of QTERNMET XR
`
`
`
`2.2 Dosage
`
`
`2.3 Patients with Renal Impairment
`
`
`
`2.4 Use with Strong CYP3A4/5 Inhibitors
`
`
`
`2.5 Discontinuation for Iodinated Contrast Imaging Procedures
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Lactic Acidosis
`
`
`5.2 Pancreatitis
`
`
`5.3 Heart Failure
`
`
`5.4 Hypotension
`
`
`5.5 Ketoacidosis
`
`
`5.6 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`
`
`
`5.7 Urosepsis and Pyelonephritis
`
`5.8 Hypoglycemia with Concomitant Use of Insulin or Insulin
`
`
`
`Secretagogues
`
`5.9 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`
`
`
`5.10 Hypersensitivity Reactions
`
`
`5.11 Vitamin B12 Concentrations
`
`
`
`5.12 Genital Mycotic Infections
`
`
`
`5.13 Increases in Low-Density Lipoprotein Cholesterol (LDL–C)
`
`
`
`
`5.14 Bladder Cancer
`
`
`5.15 Severe and Disabling Arthralgia
`
`
`5.16 Bullous Pemphigoid
`
`
`5.17 Macrovascular Outcomes
`
`ADVERSE REACTIONS
`
`
`6
`
`Reference ID: 4456142
`
`
`
` 2
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: LACTIC ACIDOSIS
`
`• Postmarketing cases of metformin-associated lactic acidosis have resulted in death,
`
`
`
`
`hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin­
`
`associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
`malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin­
`associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter),
`
`
`
`
`anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate
`
`
`ratio; and metformin plasma levels generally >5 mcg/mL [see WARNINGS AND
`
`
`
`PRECAUTIONS (5.1)].
`
`
`• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant
`
`
`
`use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old
`
`
`
`
`
`or greater, having a radiological study with contrast, surgery and other procedures, hypoxic
`
`
`
`states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
`
`
`
`
`• Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk
`
`
`
`
`
`
`groups are provided in the full prescribing information [see DOSAGE AND
`
`
`ADMINISTRATION (2.2), CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS
`
`
`
`(5.1), DRUG INTERACTIONS (7) and USE IN SPECIFIC POPULATIONS (8.6, 8.7)].
`
`
`
`• If metformin-associated lactic acidosis is suspected, immediately discontinue QTERNMET XR
`
`
` and institute general supportive measures in a hospital setting. Prompt hemodialysis is
`
`
`
`
` recommended [see WARNINGS AND PRECAUTIONS (5.1)].
`
`
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
` QTERNMET XR (dapagliflozin, saxagliptin, and metformin hydrochloride) extended-release tablets is
`
`
`
`
`
`
`
` indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`
` mellitus.
`
`
`
` Limitations of Use
`
`
`
`
`QTERNMET XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`
`
`
`
`
`
`QTERNMET XR initiation is intended only for patients currently taking metformin.
`
`
`
`
`
`
`
`
`
` 2
`
`
`
` DOSAGE AND ADMINISTRATION
`
` 2.1
`
`
`
`
` Prior to Initiation of QTERNMET XR
`
` Assess renal function before initiating QTERNMET XR therapy and periodically thereafter [see
`
`
`
` WARNINGS AND PRECAUTIONS (5.1, 5.6) and USE IN SPECIFIC POPULATIONS (8.5, 8.6)].
`
`
`
`
`
` In patients with volume depletion, correct this condition prior to initiation of QTERNMET XR [see
`
`
`
` WARNINGS AND PRECAUTIONS (5.4, 5.6) and USE IN SPECIFIC POPULATIONS (8.5, 8.6)].
`
`
`
`
`
`
`Reference ID: 4456142
`
`
`3
`
`

`

`
`
` 2.2
`
`
` Dosage
`
`
` Individualize the starting total daily dose of QTERNMET XR based on the patient’s current regimen,
` effectiveness, and tolerability [see DOSAGE FORMS AND STRENGTHS (3)].
`
`
`
`
`
`
`
`
`
`Take QTERNMET XR orally, once daily in the morning with food.
`
`
`
`For patients not currently taking dapagliflozin, the recommended starting total daily dose of QTERNMET
`
`XR is a 5 mg dapagliflozin/5 mg saxagliptin/1000 mg or 2000 mg metformin hydrochloride (HCl)
`
`
`
`
`
`
`
`
`
`extended-release once daily.
`
`
`
`The maximum recommended daily dose is10 mg dapagliflozin, 5 mg saxagliptin, and 2000 mg metformin
`
`
`
`
`HCl extended-release.
`
`
`
`Swallow whole. Do not crush, cut or chew the QTERNMET XR tablet. Occasionally, the inactive
`
`
`
`
`ingredients of QTERNMET XR will be eliminated in the feces as a soft, hydrated mass that may resemble
`
`
`
`
`the original tablet.
`
`
`
`If a daily dose is missed and it is greater than or equal to 12 hours until the next dose, the dose should be
`
`
`
`
`taken. If a daily dose is missed and it is less than 12 hours until the next dose, the missed dose should be
`
`
`
`
`skipped and the next dose taken at the usual time.
`
`
` 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.
`
`
`
`
`
`QTERNMET XR 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)].
`
`
` Use with Strong CYP3A4/5 Inhibitors
` 2.4
`
`
`
` Do not coadminister QTERNMET XR with strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole,
`atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and
`telithromycin) [see DRUG INTERACTIONS (7)].
`
`
`
` 2.5
`
`
`
` Discontinuation for Iodinated Contrast Imaging Procedures
`
` Discontinue QTERNMET XR at the time of, or prior to, an iodinated contrast imaging procedure in
`
`
` patients with a history of liver disease, alcoholism or heart failure, or in patients who will be administered
`
`
`
`
`
` intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart
`
`
`
`
`
` QTERNMET XR if renal function is stable [see WARNINGS AND PRECAUTIONS (5.1)].
`
`
`
`
`
`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` Extended-Release Tablets:
`
`
`
`Reference ID: 4456142
`
`
`4
`
`

`

`
`
`
` Dapagliflozin
`
` Strength
`
`
` 2.5 mg
`
`
` Saxagliptin
`
` Strength
`
`
` 2.5 mg
`
`Metformin HCl
`
` Strength
`
`
` 1000 mg
`
`
`
` 5 mg
`
`
`
`
`
` 2.5 mg
`
`
`
`
`
` 5 mg
`
`
`
`
`
` 10 mg
`
`
`
`
`
` 5 mg
`
`
`
`
`
` 5 mg
`
`
`
`
`
` 1000 mg
`
`
`
`
`
` 1000 mg
`
`
`
`
`
` 1000 mg
`
`
`
`
`
` * Debossed on one side.
`
`
`
` 4
`
`
`
` CONTRAINDICATIONS
`
`
`
` Color/Shape
`
` light brown to brown,
`
` biconvex, oval, film-coated
`
`
` tablet
`green, biconvex, oval, film-
`
` coated tablet
`pink, biconvex, oval, film-
`
` coated tablet
`gray, biconvex, oval, film-
`
` coated tablet
`
` Tablet
`
`
` Identifiers*
`
` 3001
`
`
`
` 3002
`
`
`
` 3003
`
`
`
` 3004
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` QTERNMET XR is contraindicated in patients with:
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` • History of a serious hypersensitivity reaction to dapagliflozin, saxagliptin, or metformin, including
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` anaphylaxis, angioedema, or exfoliative skin conditions [see WARNINGS AND PRECAUTIONS
`
` (5.10) and ADVERSE REACTIONS (6.1)].
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` • Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end-stage renal disease
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`(ESRD), or patients on dialysis [see USE IN SPECIFIC POPULATIONS (8.6)].
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`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic
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`ketoacidosis should be treated with insulin [see WARNINGS AND PRECAUTIONS (5.1) and
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`ADVERSE REACTIONS (6.1)].
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` 5
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` WARNINGS AND PRECAUTIONS
`
` Lactic Acidosis
` 5.1
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` There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases.
` These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,
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` myalgias, abdominal pain, respiratory distress or increased somnolence; however, hypothermia,
` hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
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` Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations
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` (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased
` lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake
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`
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` of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in
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` patients at risk.
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`If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted
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` promptly in a hospital setting, along with immediate discontinuation of QTERNMET XR.
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`Reference ID: 4456142
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`5
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`

`

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`In QTERNMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt
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`hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin
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`hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic
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`conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
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`Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur
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`instruct them to discontinue QTERNMET XR and report these symptoms to their healthcare provider.
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`For each of the known and possible risk factors for metformin-associated lactic acidosis,
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`recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided
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`below:
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`Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in
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`patients with significant renal impairment. The risk of metformin accumulation and metformin-associated
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`lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted
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`by the kidney. Clinical recommendations [see DOSAGE AND ADMINISTRATION (2.2) and CLINICAL
`PHARMACOLOGY (12.3)] based upon the patient’s renal function include:
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`• Before initiating QTERNMET XR, obtain an estimated glomerular filtration rate (eGFR).
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`• Obtain an eGFR at least annually in all patients taking QTERNMET XR. In patients at increased risk
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`for the development of renal impairment (e.g., the elderly), renal function should be assessed more
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`frequently.
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`• QTERNMET XR is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2 [see
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`CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.6)].
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`Drug Interactions: The concomitant use of QTERNMET XR with specific drugs may increase the risk of
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`metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic
`change, interfere with acid-base balance, or increase metformin accumulation (e.g., cationic drugs) [see
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`DRUG INTERACTIONS (7)]. Therefore, consider more frequent monitoring of patients.
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`Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age
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`because elderly patients have a greater likelihood of having hepatic, renal or cardiac impairment than
`younger patients. Assess renal function more frequently in elderly patients [see USE IN SPECIFIC
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`POPULATIONS (8.5)].
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`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in
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`metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic
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`acidosis. Stop QTERNMET XR at the time of, or prior to, an iodinated contrast imaging procedure in
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`patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be
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`administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure,
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`and restart QTERNMET XR if renal function is stable.
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`Reference ID: 4456142
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`6
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`Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may
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`increase the risk for volume depletion, hypotension and renal impairment. QTERNMET XR should be
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`temporarily discontinued while patients have restricted food and fluid intake.
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`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in
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`the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and
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`hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis and other conditions
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`associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal
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`azotemia. When such events occur, discontinue QTERNMET XR.
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`Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may
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`increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake
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`while receiving QTERNMET XR.
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`Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin­
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`associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood
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`levels. Therefore, avoid use of QTERNMET XR in patients with clinical or laboratory evidence of
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`hepatic disease.
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` 5.2
` Pancreatitis
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`
`
` 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%)
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` receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those
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` patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo.
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` After initiation of QTERNMET XR, observe patients for signs and symptoms of pancreatitis. If
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` pancreatitis is suspected, promptly discontinue QTERNMET XR and initiate appropriate management. It
` is unknown whether patients with a history of pancreatitis are at increased risk for the development of
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` pancreatitis while using QTERNMET XR.
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` 5.3 Heart Failure
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` In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors
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`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
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`analysis, the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard
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`Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal
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`impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment.
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`Consider the risks and benefits of QTERNMET XR prior to initiating treatment in patients at a higher risk
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`of heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients
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`of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure
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`Reference ID: 4456142
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`7
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`

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`develops, evaluate and manage according to current standards of care and consider discontinuation of
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`QTERNMET XR.
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` 5.4 Hypotension
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` Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after
` initiating QTERNMET XR [see ADVERSE REACTIONS (6.1)] particularly in patients with impaired
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` renal function (eGFR <60 mL/min/1.73 m2), elderly patients or patients on loop diuretics. Before
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`initiating QTERNMET XR, volume status should be assessed and corrected. QTERNMET XR is
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`contraindicated in patients with an eGFR <45 mL/min/1.73 m2. Monitor for signs and symptoms of
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`hypotension after initiating therapy.
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` 5.5 Ketoacidosis
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` 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
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` sodium glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin. Fatal cases of ketoacidosis
` have been reported in patients taking dapagliflozin. QTERNMET XR is not indicated for the treatment of
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` patients with type 1 diabetes mellitus [see INDICATIONS AND USAGE (1)].
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`Patients treated with QTERNMET XR who present with signs and symptoms consistent with severe
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`metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as
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`ketoacidosis associated with QTERNMET XR may be present even if blood glucose levels are less than
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`250 mg/dL. If ketoacidosis is suspected, QTERNMET XR should be discontinued, the patient should be
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`evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid
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`and carbohydrate replacement.
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`In many of the postmarketing reports for dapagliflozin, and particularly in patients with type 1 diabetes,
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`the presence of ketoacidosis was not immediately recognized and the institution of treatment was delayed
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`because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis
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`(often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and
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`severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and
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`shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose
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`reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders
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`suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and
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`alcohol abuse were identified.
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`Before initiating QTERNMET XR, consider factors in the patient history that may predispose to
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`ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction and alcohol abuse.
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`In patients treated with QTERNMET XR consider monitoring for ketoacidosis and temporarily
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`discontinuing QTERNMET XR in clinical situations known to predispose to ketoacidosis (e.g., prolonged
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`fasting due to acute illness or surgery) [see ADVERSE REACTIONS (6.2)].
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` 5.6
` Acute Kidney Injury and Impairment in Renal Function
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` Dapagliflozin causes intravascular volume contraction [see WARNINGS AND PRECAUTIONS (5.4)] and
`
` can cause renal impairment [see ADVERSE REACTIONS (6.1)]. There have been postmarketing reports
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`Reference ID: 4456142
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`
`8
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`

`

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`of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving dapagliflozin;
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`some reports involved patients younger than 65 years of age.
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`Before initiating QTERNMET XR, consider factors that may predispose patients to acute kidney injury
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`including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications
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`(diuretics, ACE inhibitors, ARBs and NSAIDs). Consider temporarily discontinuing QTERNMET XR in
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`any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (gastrointestinal illness
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`or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute
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`kidney injury occurs, discontinue QTERNMET XR promptly and institute treatment.
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`Dapagliflozin increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired
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`renal function may be more susceptible to these changes. Adverse reactions related to renal function can
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`occur after initiating QTERNMET XR [see ADVERSE REACTIONS (6.1)]. Renal function should be
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`evaluated prior to initiation of QTERNMET XR and monitored periodically thereafter. QTERNMET XR
`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)].
`
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` 5.7
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`
` Urosepsis and Pyelonephritis
`
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` There have been postmarketing reports of serious urinary tract infections including urosepsis and
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` pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including dapagliflozin.
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` Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs
`
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` and symptoms of urinary tract infections and treat promptly, if indicated [see ADVERSE REACTIONS
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` (6.2)].
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` 5.8