GLUCOPHAGE Tablet / Extended-release tablet Ref.[10564] 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, 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 GLUCOPHAGE/GLUCOPHAGE XR. In GLUCOPHAGE/GLUCOPHAGE 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/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 GLUCOPHAGE/GLUCOPHAGE 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 (2.1) andClinical Pharmacology (12.3)].
• Before initiating GLUCOPHAGE/GLUCOPHAGE XR, obtain an estimated glomerular filtration rate (eGFR).
• GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² [see Contraindications (4)]
• Initiation of GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with eGFR between 30-45 mL/min/1.73 m².
• Obtain an eGFR at least annually in all patients taking GLUCOPHAGE/GLUCOPHAGE XR. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR falls below 45 mL/min/1.73 m², assess the benefit and risk ofcontinuing therapy.
• Drug interactions — The concomitant use of GLUCOPHAGE/GLUCOPHAGE 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. 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 GLUCOPHAGE/GLUCOPHAGE XR 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart GLUCOPHAGE/GLUCOPHAGE 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. GLUCOPHAGE/GLUCOPHAGE 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 cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE/GLUCOPHAGE XR.
• Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.
• 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 GLUCOPHAGE/GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B₁₂ Deficiency

In GLUCOPHAGE clinical trials of 29-week duration, 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 GLUCOPHAGE 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 GLUCOPHAGE/GLUCOPHAGE XR 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. GLUCOPHAGE/GLUCOPHAGE XR 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 GLUCOPHAGE/GLUCOPHAGE XR [see Drug Interactions (7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOPHAGE/GLUCOPHAGE XR.

The following adverse reactions are also discussed elsewhere in 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.

GLUCOPHAGE

In a U.S. clinical trial of GLUCOPHAGE in patients with type 2 diabetes mellitus, a total of 141 patients received GLUCOPHAGE up to 2550 mg per day. Adverse reactions reported in greater than 5% of GLUCOPHAGE treated patients and that were more common than in placebo-treated patients, are listed in Table 1.

Table 1. Adverse Reactions from a Clinical Trial of GLUCOPHAGE Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus:

Diarrhea led to discontinuation of GLUCOPHAGE in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of GLUCOPHAGE treated patients and were more commonly reported with GLUCOPHAGE than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

In GLUCOPHAGE clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of patients.

Pediatric Patients

In clinical trials with GLUCOPHAGE in pediatric patients with type 2 diabetes
mellitus, the profile of adverse reactions was similar to that observed in adults.

GLUCOPHAGE XR

In placebo-controlled trials, 781 patients were administered GLUCOPHAGE XR. Adverse reactions reported in greater than 5% of the GLUCOPHAGE XR patients, and that were more common in GLUCOPHAGE XR- than placebo-treated patients, are listed in Table 2.

Table 2. Adverse Reactions from Clinical Trials of GLUCOPHAGE XR Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus:

Diarrhea led to discontinuation of GLUCOPHAGE XR in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of GLUCOPHAGE XR patients and were more commonly reported with GLUCOPHAGE XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

The following adverse reactions have been identified during post approval use of metformin. 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 3 presents clinically significant drug interactions with GLUCOPHAGE/GLUCOPHAGE XR.

Table 3. Clinically Significant Drug Interactions with GLUCOPHAGE/GLUCOPHAGE XR:

Risk Summary

Limited data with GLUCOPHAGE/GLUCOPHAGE XR 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 2- and 5- times, respectively, a 2550 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, 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 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

Metformin hydrochloride 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 2 and 5 times a 2550 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.

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 GLUCOPHAGE/GLUCOPHAGE XR and any potential adverse effects on the breastfed child from GLUCOPHAGE/GLUCOPHAGE XR 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 GLUCOPHAGE/GLUCOPHAGE XR may result in ovulation in some anovulatory women.

GLUCOPHAGE

The safety and effectiveness of GLUCOPHAGE for the treatment of type 2 diabetes mellitus have been established in pediatric patients 10 to 16 years old. Safety and effectiveness of GLUCOPHAGE have not been established in pediatric patients less than 10 years old.

Use of GLUCOPHAGE in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes mellitus is supported by evidence from adequate and well-controlled studies of GLUCOPHAGE in adults with additional data from a controlled clinical study in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults [see Clinical Studies (14.1)]. In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2000 mg of GLUCOPHAGE is recommended [See Dosage and Administration (2.2)].

GLUCOPHAGE XR

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

Controlled clinical studies of GLUCOPHAGE/GLUCOPHAGE XR did not include sufficient numbers of elderly patients to determine whether they respond differently from younger 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 lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (15)].

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].