GLUMETZA Film coated tablet, extended release Ref.[10822] Active ingredients: Metformin

5.1 Lactic Acidosis

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 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 GLUMETZA. In GLUMETZA-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/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 GLUMETZA 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 GLUMETZA, obtain an estimated glomerular filtration rate (eGFR).
  • GLUMETZA is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m² [see Contraindications (4)].
  • Initiation of GLUMETZA is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m².
  • Obtain an eGFR at least annually in all patients taking GLUMETZA. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking GLUMETZA whose eGFR later falls below 45 mL/minute/1.73 m², assess the benefit and risk of continuing therapy.
• Drug Interactions: The concomitant use of GLUMETZA 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 [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 [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 GLUMETZA at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/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 GLUMETZA 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. GLUMETZA 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 GLUMETZA.
• 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 GLUMETZA.
• 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 GLUMETZA in patients with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B₁₂ Deficiency

In clinical trials 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 GLUMETZA and manage any abnormalities [see Adverse Reactions (6.1)].

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. GLUMETZA may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with GLUMETZA [see Drug Interactions (7)].

5.4 Macrovascular Outcomes

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

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Vitamin B₁₂ Deficiency [see Warnings and Precautions (5.2)]
• Hypoglycemia [see Warnings and Precautions (5.3)]

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 practice. In clinical trials conducted in the U.S., over 1,000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1,500 to 2,000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form.

In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA and glyburide and 144 patients received placebo and glyburide. Adverse reactions reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA and glyburide group than in the placebo and glyburide group are shown in Table 1.

In 0.7% of patients treated with GLUMETZA and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group.

Table 1. Adverse Reactions Reported by >5%* of Patients for the Combined GLUMETZA Groups Versus Placebo Group:

Laboratory Tests

Vitamin B₁₂ Concentrations

In clinical trials 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.

The following adverse reactions have been identified during post-approval use of GLUMETZA. 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.

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

Table 2 presents clinically significant drug interactions with GLUMETZA.

Table 2. Clinically Significant Drug Interactions with GLUMETZA:

Risk Summary

Limited data with GLUMETZA 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 [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].

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 1 times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6–10% in women with pregestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20–25% in women with an 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, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Data

Human Data

Published data from postmarketing 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

Metformin HCl was not teratogenic or embyrolethal when administered to rats prior to pregnancy through the period of organogenesis at doses up to 900 mg/kg, or when administered to rabbits during the period of organogenesis at doses up to 90 mg/kg.

Risk Summary

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 GLUMETZA and any potential adverse effects on the breastfed child from GLUMETZA or from the underlying maternal condition.

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.

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

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

Clinical studies of GLUMETZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUMETZA is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m² [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis.

GLUMETZA is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].