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Label Changes for:

Synjardy (empagliflozin and metformin hydrochloride)

July 2016

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

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

July 2016

BOX WARNING (revised as below)

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., 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.  If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

CONTRAINDICATIONS

SYNJARDY is contraindicated in patients with (revised bullet)

  • Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or dialysis.

WARNINGS AND PRECAUTIONS

Ketoacidosis

(addition of the following sentence)

  • Fatal cases of ketoacidosis have been reported in patients taking empagliflozin.
Lactic Acidosis (entire section revised)
  • There have been postmarketing 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 SYNJARDY. In SYNJARDY-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 SYNJARDY 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 SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).
      • SYNJARDY is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2.
      • Obtain an eGFR at least annually in all patients taking SYNJARDY. 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 SYNJARDY 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). 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 SYNJARDY at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; 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 SYNJARDY 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. SYNJARDY 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 SYNJARDY.
  • 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 SYNJARDY.
  • Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY in patients with clinical or laboratory evidence of hepatic disease.
Drug Interactions with Metformin Hydrochloride
Drugs that Reduce Metformin Clearance (additional subsection added)
  • 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 the risk for lactic acidosis. Consider more frequent monitoring of these patients.
Carbonic Anhydrase Inhibitors (additional sentences)
  • 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 SYNJARDY may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients.
Alcohol (additional section)
  • Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving SYNJARDY.

USE IN SPECIFIC POPULATIONS

  • PLLR Conversion; please refer to label.
Geriatric Use
  • … renal function should be assessed more frequently in elderly patients replaces monitor renal function more frequently after initiating SYNJARDY in the elderly and then adjust dose based on renal function
Metformin hydrochloride
  • ... 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.
Renal Impairment
Metformin hydrochloride
  • … SYNJARDY is contraindicated in moderate to severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2.
Hepatic Impairment
Metformin hydrochloride (revised as below)
  • Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY is not recommended in patients with hepatic impairment.

PATIENT COUNSELING INFORMATION

Lactic Acidosis (new subsection heading)
  • Inform patients of the risks of lactic acidosis…
Monitoring of Renal Function (replaces the former heading Laboratory Tests)
  • Inform patients about the importance of regular testing of renal function when receiving treatment with SYNJARDY.
  • (addition) Instruct patients to inform their doctor that they are taking SYNJARDY prior to any surgical or radiological procedure, as temporary discontinuation of SYNJARDY may be required until renal function has been confirmed to be normal.
Hypoglycemia
  • Inform patients that the risk of hypoglycemia is increased when SYNJARDY is used in combination with an insulin secretagogue (e.g., sulfonylurea), and that a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.
Pregnancy
  • Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with SYNJARDY. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.
Lactation
  • Advise women that breastfeeding is not recommended during treatment with SYNJARDY.
Females and Males of Reproductive Potential
  • Inform females that treatment with metformin may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy
Missed Dose
  • Instruct patients to take SYNJARDY only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.            
Blood Glucose and A1C Monitoring
  • Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels toward the normal range. Hemoglobin A1c monitoring is especially useful for evaluating long-term glycemic control.

MEDICATION GUIDE

What is the most important information I should know about SYNJARDY?

  • Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with SYNJARDY if you: …
  • … 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 SYNJARDY for a while if you have any of these things.

(addition of the following bullet)

  • are a premenopausal woman (before the “change of life”), who does not have periods regularly or at all. Talk to your doctor about birth control choices while taking SYNJARDY if you are not planning to become pregnant since SYNJARDY may increase your chance of becoming pregnant. Tell your doctor right away if you become pregnant while taking SYNJARDY.
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