Drug Safety-related Labeling Changes (SrLC)

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GLUCOVANCE (NDA-021178)

(GLYBURIDE; METFORMIN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/27/2018 (SUPPL-18)

Approved Drug Label (PDF)

Boxed Warning

Boxed Warning

(Physician Labeling Rule (PLR) Conversion)

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.

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

4 Contraindications

4 CONTRAINDICATIONS

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)


GLUCOVANCE is contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73 m2).

  • Hypersensitivity to metformin or glyburide.

  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

  • Concomitant administration of bosentan.

5 Warnings and Precautions

5.1 Lactic Acidosis

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin- associated  lactic  acidosis  was  characterized  by  elevated  blood  lactate  concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were 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 GLUCOVANCE. In GLUCOVANCE treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable with a clearance of up to 170 mL/min 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 GLUCOVANCE 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:

      • Before initiating GLUCOVANCE, obtain an estimated glomerular filtration rate (eGFR).

      • GLUCOVANCE is contraindicated in  patients  with  an  eGFR  less  than 30 mL/min/1.73 m2.

      • Initiation of GLUCOVANCE is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.

      • Obtain an eGFR at least annually in all patient taking GLUCOVANCE. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

      • In patients taking GLUCOVANCE whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

         

  • Drug interactions—The concomitant use of GLUCOVANCE 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. 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.

           

        • Radiologic studies with contrastAdministration 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 GLUCOVANCE at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 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. Reevaluate eGFR 48 hours after the imaging procedure, and restart GLUCOVANCE 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. GLUCOVANCE should be temporarily discontinued while patients have restricted food and fluid intake.

 

        • Hypoxic statesSeveral 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 cause prerenal azotemia. When such an event occurs, discontinue GLUCOVANCE.

           

        • Excessive Alcohol intake—Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake, acute or chronic, while receiving GLUCOVANCE.

           

        • Hepatic impairmentPatients 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 GLUCOVANCE in patients with clinical or laboratory evidence of hepatic disease.

 

5.2 Hypoglycemia

(Physician Labeling Rule (PLR) Conversion)

 

All sulfonylurea drugs, including GLUCOVANCE, are capable of producing severe hypoglycemia [see Adverse Reactions (6)]. Concomitant use of GLUCOVANCE with other anti- diabetic medication can increase the risk of hypoglycemia. A lower dose of GLUCOVANCE may be required to minimize the risk of hypoglycemia when combining it with other anti- diabetic medications.

Educate patients to recognize and manage hypoglycemia. When initiating and increasing GLUCOVANCE in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications) start with a lower dose. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.

The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.

 

These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.

 

 

 

5.3                                     Cardiovascular Mortality

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical study designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes mellitus. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups.

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

 

 

 

5.4         Hemolytic Anemia

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including GLUCOVANCE, can lead to hemolytic anemia. Avoid use of GLUCOVANCE in patients with G6PD deficiency. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

 

 

 

5.5                                     Vitamin B12 Deficiency

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

In clinical studies of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B12 levels, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor  complex,  may  be  associated  with  anemia  but  appears  to  be  rapidly  reversible  with discontinuation of metformin or vitamin B12  supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on GLUCOVANCE and manage any abnormalities.

 

 

 

5.6                                     Macrovascular Outcomes

(Physician Labeling Rule (PLR) Conversion)

 

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOVANCE.

6 Adverse Reactions

6 Adverse Reactions

(Physician Labeling Rule (PLR) Conversion)

 

The following adverse reactions are also discussed elsewhere in the labeling:

  • Lactic Acidosis

  • Hypoglycemia

  • Cardiovascular mortality

  • Hemolytic anemia

Vitamin B12 Deficiency

 

 

 

6.1                                     Clinical Studies Experience

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

(Table 1 and 2 has been revised; please refer to label)

 

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.


In double-blind clinical studies with GLUCOVANCE as initial therapy or as second-line therapy of 20 and 14 weeks, respectively (see section 14), a total of 642 patients received GLUCOVANCE, 312 received metformin HCl, 324 received glyburide, and 161 received placebo. Adverse reactions are listed in Table 1.

Hypoglycemia


The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy study of GLUCOVANCE are summarized in Table 2. For patients with a baseline HbA1c between 8% and 11% treated with GLUCOVANCE 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with GLUCOVANCE experienced hypoglycemic symptoms.

 

Gastrointestinal Reactions


The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the GLUCOVANCE initial therapy study are summarized in Table 2. Across all GLUCOVANCE studies, GI symptoms were the most common adverse events with GLUCOVANCE and were more frequent at higher dose levels. In controlled studies, <2% of patients discontinued GLUCOVANCE therapy due to GI adverse events.

 

Dermatologic Reactions

 

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use.



6.2                                     Postmarketing Adverse Reactions

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

The following adverse reactions have been identified during post-approval use of GLUCOVANCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.


Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.

 

Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

 

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.

 

Hepatic: Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

 

Cholestatic jaundice and hepatitis may occur rarely with glyburide, which may progress to liver failure. Liver function abnormalities, including isolated transaminase elevations, have been reported.

 

Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

 

Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

7 Drug Interactions

7 DRUG INTERACTIONS

(Physician Labeling Rule (PLR) Conversion; table 3 has been revised; please refer to label)

 

Table 3 presents clinically significant drug interactions with GLUCOVANCE.


8 Use in Specific Populations

8.1 Pregnancy

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

Risk Summary


Available data from a small number of published studies and postmarketing experience with glyburide use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glyburide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, GLUCOVANCE should be discontinued at least two weeks before expected delivery. Limited data with metformin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk.. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy.


No evidence of harm to the fetus was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area, were administered to rats and rabbits in reproduction studies.


No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 3- and 6- times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].


The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.


Clinical Considerations


Disease-associated maternal and/or embryo/fetal risk


Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.


Fetal/Neonatal Adverse Reactions


Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.


Dose adjustments during pregnancy and the postpartum period


Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, GLUCOVANCE should be discontinued at least two weeks before expected delivery.


Data


Human Data


Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

 

Animal Data

 

Reproduction studies were performed in rats and rabbits at doses up to 500 times the maximum recommended human dose of 20 mg of glyburide based on body surface area comparisons and revealed no evidence of harm to the fetus.


Metformin did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 3 and 6 times a 2000 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

 


8.2         Lactation

(Physician Labeling Rule (PLR) Conversion)

 

Risk Summary

 

Breastfed infants of lactating women using GLUCOVANCE should be monitored for symptoms of hypoglycemia [see Clinical Considerations]. Although glyburide was negligible in human milk in one small clinical lactation study; this result is not conclusive because of the limitations of the assay used in the study. There are no data on the effects of glyburide on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GLUCOVANCE and any potential adverse effects on the breastfed child from GLUCOVANCE or from the underlying maternal condition.

 

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Data

 

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

 

 

8.3                                     Females and Males of Reproductive Potential

(Physician Labeling Rule (PLR) Conversion)

 

Discuss the potential for unintended pregnancy with premenopausal women as therapy with GLUCOVANCE may result in ovulation in some anovulatory women.

 

  

8.4                                     Pediatric Use

(Physician Labeling Rule (PLR) Conversion)

 

Safety and effectiveness of GLUCOVANCE have not been established in pediatric patients.

 

  

8.5         Geriatric Use

(Physician Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)

 

Of the 642 patients who received GLUCOVANCE in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents. Hypoglycemia may be difficult to recognize in these patients.


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 hypoglycemia and lactic acidosis. Assess renal function more frequently in elderly patients.


 

8.6                                     Renal Impairment

(Physician Labeling Rule (PLR) Conversion)

 

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUCOVANCE is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

 

 

 

8.7       Hepatic Impairment

(Physician Labeling Rule (PLR) Conversion)

 

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUCOVANCE is not recommended in patients with hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Physician Labeling Rule (PLR) Conversion)

 

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Lactic Acidosis:

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue GLUCOVANCE immediately and to promptly notify their healthcare provider practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving GLUCOVANCE. Instruct patients to inform their doctor that they are taking GLUCOVANCE prior to any surgical or radiological procedure, as temporary discontinuation may be required.

Hypoglycemia:

Inform patients that hypoglycemia may occur when taking GLUCOVANCE. Explain to patients the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development.

Cardiovascular Mortality:

Inform patients that the administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Inform patients of the potential risks and benefits of glyburide and of alternative modes of therapy.

Vitamin B12 Deficiency:

Inform patients about importance of regular hematological testing while receiving GLUCOVANCE.

 Females of Reproductive Age:

 Inform females that treatment with GLUCOVANCE may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy.

 


Other

PATIENT INFORMATION

(Format changed, please refer to the label)

 

04/05/2017 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

Metformin Hydrochloride

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

 

Glyburide

         


Gastrointestinal Reactions

Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; the drug should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported.

 

Dermatologic Reactions

Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use; if skin reactions persist, the drug should be discontinued.

Postmarketing Adverse Reactions

(subsection added)

The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.

Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.

Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

04/05/2017 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

GLUCOVANCE is contraindicated in patients with:

1.   Severe renal impairment (eGFR below 30 mL/min/1.73m2)

2.   Known hypersensitivity to metformin hydrochloride or glyburide.

3.   Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

4.   Concomitant administration of bosentan.

5 Warnings and Precautions

PRECAUTIONS

(additions underlined)

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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin- associated   lactic   acidosis   was   characterized   by   elevated   blood   lactate   concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased   lactate:pyruvate   ratio;   metformin   plasma   levels   were   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 GLUCOVANCE. In GLUCOVANCE 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/min 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 GLUCOVANCE 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:


•       Before initiating GLUCOVANCE, obtain an estimated glomerular filtration rate

(eGFR).

•       GLUCOVANCE is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2

•       Initiation of GLUCOVANCE is not recommended in patients with eGFR

between 30-45 mL/min/1.73 m2.

•       Obtain an eGFR at least annually in all patient taking GLUCOVANCE. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

•       In patients taking GLUCOVANCE whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.


  • Drug interactions—The concomitant use of GLUCOVANCE 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. 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.
  • Radiologic 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 GLUCOVANCE at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 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. Reevaluate eGFR 48 hours after the imaging procedure, and restart GLUCOVANCE 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. GLUCOVANCE 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 cause prerenal azotemia. When such an event occurs, discontinue GLUCOVANCE.
  • Excessive Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving GLUCOVANCE.




  • 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 GLUCOVANCE in patients with clinical or laboratory evidence of hepatic disease.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOVANCE or any other antidiabetic drug.

WARNING

(subsection revised, additions underlined)

Post-marketing 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.

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

7 Drug Interactions

Alcohol

Alcohol is known to potentiate the effects of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving GLUCOVANCE.

Carbonic Anhydrase Inhibitors

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 GLUCOVANCE may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs that reduce metformin clearance

(additions underlined)

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transport-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the accumulation of metformin and the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly   protein-bound   drugs   such   as   salicylates,   sulfonamides,   chloramphenicol,   and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

8 Use in Specific Populations

Geriatric Use

(additions underlined)

Of the 642 patients who received GLUCOVANCE in double-blind clinical studies, 23.8% were65 and older while 2.8% were 75 and older. Of the 1302 patients who received GLUCOVANCE in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(revisions and additions, please refer to label)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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