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Label Changes for:

Xigduo XR (dapagliflozin and metformin HCl extended-release)

June 2016

Changes have been made to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

June 2016

BOX WARNING (extensively updated, please refer to label)

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.
  • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs 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.
  • If metformin-associated lactic acidosis is suspected, immediately discontinue XIGDUO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

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. (Replaces previous first bullet in section)

WARNINGS AND PRECAUTIONS

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.
    • 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.
    • 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.
  • 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.
  • 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.
Acute Kidney Injury and Impairment in Renal Function
  • Dapagliflozin causes intravascular volume contraction, and can cause renal impairment. 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. 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.

ADVERSE REACTIONS

(addition of the following two bullets)

  • Lactic Acidosis
  • Acute Kidney Injury and Impairment in Renal Function
Postmarketing Experience

Acute Kidney Injury and Impairment in Renal Function (addition)

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors (addition)
  • Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with XIGDUO XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance (addition)
  • Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and risk for lactic acidosis. Consider more frequent monitoring of these patients.
Alcohol (addition)
  • Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving XIGDUO XR.

USE IN SPECIFIC POPULATIONS

Geriatric Use
Metformin hydrochloride (updated)
  • Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of lactic acidosis with metformin is greater in patients with moderately to severely impaired renal function. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.
Hepatic Impairment (addition)
  • Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment.

PATIENT COUNSELING INFORMATION

Acute Kidney Injury
  • Inform patients that acute kidney injury has been reported during use of dapagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (due to acute illness or fasting) or increased fluid losses (due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue XIGDUO XR use in those settings.

MEDICATION GUIDE

What is the most important information I should know about XIGDUO XR?

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

  • you feel cold in your hands or feet (addition of bullet)

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin use, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with XIGDUO XR if you:

  • have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.
  • have liver problems
  • drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids
  • have surgery
  • have a heart attack, severe infection, or stroke.

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your XIGDUO XR for a while if you have any of these things. XIGDUO XR can have other serious side effects. See “What are the possible side effects of XIGDUO XR?"

Who should not take XIGDUO XR?

Do not take XIGDUO XR if you:

have moderate to severe kidney problems or are on dialysis (addition of phrase)

What should I tell my healthcare provider before taking XIGDUO XR?

Before you take XIGDUO XR, tell your healthcare provider if you:

(update) have moderate to severe kidney problems

What are the possible side effects of XIGDUO XR?

XIGDUO XR may cause serious side effects including:

See “What is the most important information I should know about XIGDUO XR?”

  • kidney problems. Sudden kidney injury has happened to people taking XIGDUO XR. Talk to your doctor right away if you:
    • reduce the amount of food or liquid you drink for example, if you are sick and cannot eat or
    • you start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long.
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