HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`XIGDUO XR safely and effectively. See full prescribing information for
`XIGDUO XR.
`
`XIGDUO® XR (dapagliflozin and metformin HCl extended-release)
`tablets, for oral use
`Initial U.S. Approval: 2014
`
`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 XIGDUO XR and
`institute general supportive measures in a hospital setting. Prompt
`hemodialysis is recommended. (5.1)
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`3/2017
`Boxed Warning
`
`7/2017
`Dosing and Administration (2.1)
`
`3/2017
`Warnings and Precautions (5)
`
`
`
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`XIGDUO XR is a combination of dapagliflozin, a sodium-glucose
`cotransporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated as
`an adjunct to diet and exercise to improve glycemic control in adults with type
`2 diabetes mellitus when treatment with both dapagliflozin and metformin is
`appropriate. (1)
`Limitation of use:
`o Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`(1.1)
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`Individualize the starting dose based on the patient’s current treatment.
`
`(2.1)
`Administer once daily in the morning with food. (2.1)
`
`Swallow whole. Never crush, cut, or chew. (2.1)
`
`For patients not already taking dapagliflozin, the recommended starting
`
`dose for dapagliflozin is 5 mg once daily. (2.1)
`For patients requiring a dose of 5 mg dapagliflozin and 2000 mg
`
`metformin HCl extended-release, use two of the 2.5 mg/1000 mg
`metformin HCl extended-release tablets. (2.1)
`Do not exceed a daily dose of 10 mg dapagliflozin/2000 mg metformin
`HCl extended-release. (2.1)
`Assess renal function before initiating. Do not initiate or continue if
`eGFR is below 60 mL/min/1.73 m2. (2.2, 4)
`No dosage adjustment is indicated in patients with mild renal
`impairment. (2.2)
`XIGDUO XR may need to be discontinued at time of, or prior to,
`iodinated contrast imaging procedures. (2.3)
`
`
`
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`2.5 mg dapagliflozin/1000 mg metformin HCl extended-release (3)
`
`5 mg dapagliflozin/500 mg metformin HCl extended-release (3)
`
`5 mg dapagliflozin/1000 mg metformin HCl extended-release (3)
`
`10 mg dapagliflozin/500 mg metformin HCl extended-release (3)
`
`10 mg dapagliflozin/1000 mg metformin HCl extended-release (3)
`
`------------------------------ CONTRAINDICATIONS -----------------------------
` Moderate to severe renal impairment: (eGFR below 60 mL/min/1.73
`m2), end-stage renal disease or dialysis. (4, 5.1)
`
`Reference ID: 4131552
`
`
`
`History of serious hypersensitivity to dapagliflozin or hypersensitivity to
`
`metformin hydrochloride. (4, 6.1)
` Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Lactic acidosis: See boxed warning (2.2, 4, 5.1)
`
`Hypotension: Before initiating XIGDUO XR, assess volume status and
`
`correct hypovolemia in the elderly, in patients with renal impairment or
`low systolic blood pressure, and in patients on diuretics. Monitor for
`signs and symptoms during therapy. (5.2, 6.1)
`Ketoacidosis: Assess patients who present with signs and symptoms of
`metabolic acidosis for ketoacidosis regardless of blood glucose level. If
`suspected, discontinue XIGDUO XR, evaluate and treat promptly.
`Before initiating XIGDUO XR, consider risk factors for ketoacidosis.
`Patients on XIGDUO XR may require monitoring and temporary
`discontinuation of therapy in clinical situations known to predispose to
`ketoacidosis. (5.3)
`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. (5.4)
`Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms
`of urinary tract infections and treat promptly, if indicated. (5.5)
`Hypoglycemia: In patients taking insulin or an insulin secretagogue with
`XIGDUO XR, consider a lower dose of insulin or the insulin
`secretagogue to reduce the risk of hypoglycemia. (5.6)
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`Measure hematological parameters annually. (5.7, 6.1)
`Genital mycotic infections: Monitor and treat if indicated. (5.8)
`Increased LDL-C: Monitor and treat per standard of care. (5.9)
`Bladder Cancer: An imbalance in bladder cancers was observed in
`clinical trials. Dapagliflozin 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. (5.10)
` Macrovascular outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction with
`XIGDUO XR. (5.11)
`
`
`
`
`
`
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`The most common adverse reactions associated with XIGDUO XR (5%
`
`or greater incidence) were female genital mycotic infection,
`nasopharyngitis, urinary tract infection, diarrhea, and headache. (6.1)
`Adverse reactions reported in >5% of patients treated with metformin
`extended-release and more commonly than in patients treated with
`placebo are: diarrhea and nausea/vomiting. (6.1)
`
`
`
`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 -----------------------------
`Carbonic anhydrase inhibitors may increase the risk of lactic acidosis.
`
`Consider more frequent monitoring. (7.3)
`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. (7.4)
`Alcohol can potentiate the effect of metformin on lactate metabolism.
`Warn patients against excessive alcohol intake. (7.5)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Pregnancy: There are no adequate and well-controlled studies in
`
`pregnant women. Use during pregnancy only if the potential benefit
`justifies the potential risk to the fetus. (8.1)
`Nursing Mothers: Discontinue XIGDUO XR or discontinue nursing.
`
`(8.3)
`Geriatrics: Higher incidence of adverse reactions related to reduced
`
`intravascular volume. Assess renal function more frequently. (5.1, 8.6)
`Renal Impairment: Higher incidence of adverse reactions related to
`
`
`reduced intravascular volume and renal function. (5.1, 6.1, 8.6)
`
`Hepatic Impairment: Avoid use in patients with hepatic impairment.
`
`
`(8.7)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 7/2017
`
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`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`1 INDICATIONS AND USAGE
`1.1 Limitations of Use
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`
`2.2 Patients with Renal Impairment
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`
`5.2 Hypotension
`
`5.3 Ketoacidosis
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`
`5.5 Urosepsis and Pyelonephritis
`
`5.6 Use with Medications Known to Cause Hypoglycemia
`
`5.7 Vitamin B12 Concentrations
`
`5.8 Genital Mycotic Infections
`
`5.9 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`
`5.10 Bladder Cancer
`
`5.11 Macrovascular Outcomes
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1 Positive Urine Glucose Test
`
`7.2 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`
`7.3 Carbonic Anhydrase Inhibitors
`
`7.4 Drugs that Reduce Metformin Clearance
`
`7.5 Alcohol
`
`7.6 Use with Other Drugs
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Patients with Mild Renal Impairment (eGFR ≥60 to <90 mL/min/1.73
`
`m2)
`
`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
`
`14 CLINICAL STUDIES
`14.1 Initial Combination Therapy with Metformin Extended-Release
`
`14.2 Add-On to Metformin Immediate-Release
`
`14.3 Active Glipizide-Controlled Study Add-On to Metformin Immediate-
`
`Release
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`Reference ID: 4131552
`
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`

`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 XIGDUO XR and
`institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see
`Warnings and Precautions (5.1)].
`
`1
`
`INDICATIONS AND USAGE
`
`XIGDUO XR (dapagliflozin and metformin HCl extended-release) is indicated as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both
`dapagliflozin and metformin is appropriate [see Clinical Studies (14)].
`
`1.1 Limitations of Use
`XIGDUO XR is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.
`
`2. DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
` Healthcare providers should individualize the starting dose of XIGDUO XR based on the patient’s current
`treatment [see Dosage Forms and Strengths (3)].
` XIGDUO XR should be taken once daily in the morning with food with gradual dose escalation to reduce
`the gastrointestinal (GI) side effects due to metformin.
` XIGDUO XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the
`
`inactive ingredients of XIGDUO XR will be eliminated in the feces as a soft, hydrated mass that may
`resemble the original tablet.
` For patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is 5 mg once
`daily.
` For patients requiring a dose of 5 mg dapagliflozin and 2000 mg metformin HCl extended-release, use two
`of the 2.5 mg dapagliflozin/1000 mg metformin HCl extended-release tablets.
`
`Reference ID: 4131552
`
`3
`
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`

` Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum
`recommended daily dose of 10 mg dapagliflozin and 2000 mg metformin HCl.
` Patients taking an evening dose of metformin XR should skip their last dose before starting XIGDUO XR.
`In patients with volume depletion, correcting this condition prior to initiation of XIGDUO XR is
`
`recommended [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Patient
`Counseling Information (17)].
`
`2.2 Patients with Renal Impairment
`Assess renal function before initiating XIGDUO XR therapy and periodically thereafter.
`
`XIGDUO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below
`60 mL/min/1.73 m2 [see Contraindications (4), Warnings and Precautions (5.1, 5.4), Adverse Reactions (6.1),
`and Use in Specific Populations (8.6)].
`
`No dose adjustment for XIGDUO XR is needed in patients with mild renal impairment (eGFR of 60
`mL/min/1.73 m2 or greater).
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`Discontinue XIGDUO 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 XIGDUO XR if renal
`function is stable [see Warnings and Precautions (5.1)].
`
`3. DOSAGE FORMS AND STRENGTHS
`
`XIGDUO XR is a combination of dapagliflozin and metformin HCl extended-release. XIGDUO XR tablets are
`available in the following dosage forms and strengths:
`o 2.5 mg/1000 mg tablets are light brown to brown, biconvex, oval-shaped, and film-coated tablets with
`"1074" and "2.5/1000" debossed on one side and plain on the reverse side.
`o 5 mg/500 mg tablets are orange, biconvex, capsule-shaped, and film-coated tablets with "1070" and "5/500"
`debossed on one side and plain on the reverse side.
`o 5 mg/1000 mg tablets are pink to dark pink, biconvex, oval-shaped, and film-coated tablets with "1071" and
`"5/1000" debossed on one side and plain on the reverse side.
`o 10 mg/500 mg tablets are pink, biconvex, capsule-shaped, and film-coated tablets with "1072" and "10/500"
`debossed on one side and plain on the reverse side.
`o 10 mg/1000 mg tablets are yellow to dark yellow, biconvex, oval-shaped, and film-coated tablets with
`"1073" and "10/1000" debossed on one side and plain on the reverse side.
`
`4. CONTRAINDICATIONS
`
`XIGDUO XR is contraindicated in patients with:
`
` Moderate to severe renal impairment (eGFR below 60 mL/min/1.73 m2), end stage renal disease or patients
`on dialysis [see Warnings and Precautions (5.1)].
`
`Reference ID: 4131552
`
`4
`
`
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`

` History of a serious hypersensitivity reaction to dapagliflozin or hypersensitivity to metformin
`hydrochloride [see Adverse Reactions (6.1)].
` Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic
`ketoacidosis should be treated with insulin.
`
`5. WARNINGS AND PRECAUTIONS
`
`5.1 Lactic Acidosis
`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, myalgias, abdominal
`pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant
`bradyarrhythmias have occurred with severe acidosis.
`
`Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations
`(>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 of lactate
`increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
`
`If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly
`
`in a hospital setting, along with immediate discontinuation of XIGDUO XR.
`
`In XIGDUO XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is
`recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is
`dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has
`often resulted in reversal of symptoms and recovery.
`
`Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct
`them to discontinue XIGDUO XR and report these symptoms to their healthcare provider.
`
`For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to
`reduce the risk of and manage metformin-associated lactic acidosis are provided below:
`
`Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients
`with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis
`increases with the severity of renal impairment because metformin is substantially excreted by the kidney.
`Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration
`(2.2), and Clinical Pharmacology (12.3)]:
`
`
`
`
`
`
`Before initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).
`XIGDUO XR is contraindicated in patients with an eGFR less than 60 mL/minute/1.73 m2 [see
`Contraindications (4)].
`Obtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at increased risk for the
`development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
`
`Drug Interactions: The concomitant use of XIGDUO XR with specific drugs may increase the risk of
`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 Drug
`Interactions (7)]. Therefore, consider more frequent monitoring of patients.
`5
`
`
`Reference ID: 4131552
`
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`

`Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age 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 Populations (8.5)].
`
`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-
`treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop
`XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of
`hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated
`contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart XIGDUO XR if renal function is
`stable.
`
`Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may
`
`increase the risk for volume depletion, hypotension and renal impairment. XIGDUO XR should be temporarily
`discontinued while patients have restricted food and fluid intake.
`
`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the
`setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
`Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with
`hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events
`occur, discontinue XIGDUO XR.
`
`Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may
`
`increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while
`receiving XIGDUO XR.
`
`Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin-associated
`lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore,
`avoid use of XIGDUO XR in patients with clinical or laboratory evidence of hepatic disease.
`
`5.2 Hypotension
`Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating
`dapagliflozin [see Adverse Reactions (6.1)], particularly in patients with impaired renal function (eGFR less
`than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics.
`
`Before initiating XIGDUO XR in patients with one or more of these characteristics, volume status should be
`assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.
`
`5.3 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 taking sodium-
`glucose co transporter 2 (SGLT2) inhibitors, including dapagliflozin. Fatal cases of ketoacidosis have been
`reported in patients taking dapagliflozin. XIGDUO XR is not indicated for the treatment of patients with type 1
`diabetes mellitus [see Indications and Usage (1.1)].
`
`Patients treated with XIGDUO XR who present with signs and symptoms consistent with severe metabolic
`acidosis should be assessed for ketoacidosis regardless of blood glucose levels as ketoacidosis associated with
`XIGDUO XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected,
`XIGDUO XR should be discontinued, the patient should be evaluated and prompt treatment should be
`instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
`
`Reference ID: 4131552
`
`6
`
`
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`IPR2023-00724
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`

`In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of
`ketoacidosis was not immediately recognized and institution of treatment was delayed because 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 XIGDUO XR, 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 XIGDUO XR consider monitoring for ketoacidosis and temporarily discontinuing XIGDUO XR in clinical
`situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`Dapagliflozin causes intravascular volume contraction [see Warning and Precautions (5.1)], 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 XIGDUO XR, consider factors that may predispose patients to acute kidney injury including
`hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics,
`ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing XIGDUO XR 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
`XIGDUO XR 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 XIGDUO XR [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of
`XIGDUO XR and monitored periodically thereafter. XIGDUO XR is contraindicated in patients with an eGFR
`below 60 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and
`Precautions (5.1) and Use in Specific Populations (8.6)].
`
`5.5 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)].
`
`5.6 Use with Medications Known to Cause Hypoglycemia
`Dapagliflozin
`
`Insulin and insulin secretagogues are known to cause hypoglycemia. Dapagliflozin can increase the risk of
`hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore,
`a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when
`these agents are used in combination with XIGDUO XR.
`
`Metformin hydrochloride
`
`Reference ID: 4131552
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`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could
`occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation,
`or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
`Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol
`intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in
`the elderly and in people who are taking beta-adrenergic blocking drugs.
`
`5.7 Vitamin B12 Concentrations
`In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously
`
`normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients.
`This decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is,
`however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of
`metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is
`advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and
`managed [see Adverse Reactions (6.1)].
`
`Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed
`to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to
`3-year intervals may be useful.
`
`5.8 Genital Mycotic Infections
`Dapagliflozin increases the risk 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.
`
`5.9 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`Increases in LDL-C occur with dapagliflozin [see Adverse Reactions (6.1)]. Monitor LDL-C and treat per
`standard of care after initiating XIGDUO XR.
`
`Bladder Cancer
`5.10
`Across 22 clinical studies, 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, XIGDUO XR 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
`XIGDUO XR should be considered.
`
`5.11 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`XIGDUO XR.
`
`Reference ID: 4131552
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`6. ADVERSE REACTIONS
`
`The following important adverse reactions are described below and elsewhere in the labeling:
`
` Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
`
` Hypotension [see Warnings and Precautions (5.2)]
`
` Ketoacidosis [see Warnings and Precautions (5.3)]
`
` Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.4)]
`
` Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
`
` Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.6)]
`
` Vitamin B12 Concentrations [see Warnings and Precautions (5.7)]
`
` Genital Mycotic Infections [see Warnings and Precautions (5.8)]
`
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.9)]
`
`
` Bladder Cancer [see Warnings and Precautions (5.10)]
`
`
`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 clinical practice.
`
`Dapagliflozin and Metformin hydrochloride
`Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin
`coadministered with metformin immediate- or extended-release was used to evaluate safety. This pool included
`several add-on studies (metformin alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and
`metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients
`with cardiovascular disease [CVD] and type 2 diabetes who received their usual treatment [with metformin as
`background therapy]). For studies that included background therapy with and without metformin, only patients
`who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies 983
`patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated