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GLUCOPHAGE®
(metformin hydrochloride) Tablets
GLUCOPHAGE®^ XR
(metformin hydrochloride) Extended-Release Tablets
DESCRIPTION
GLUCOPHAGE®^ (metformin hydrochloride) Tablets and GLUCOPHAGE®^ XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride ( N,N -dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula
of C 4 H 11 N 5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble
in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.
GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient.
GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.
GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.
System Components and Performance– GLUCOPHAGE XR comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.
CLINICAL PHARMACOLOGY
Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS ) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacokinetics
Absorption and Bioavailability
The absolute bioavailability of a GLUCOPHAGE 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of GLUCOPHAGE 500 to 1500 mg, and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by
approximately a 40% lower mean peak plasma concentration (C (^) max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak
plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin
identified in humans) nor biliary excretion. Renal clearance (see Table 1 ) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Patients with Type 2 Diabetes
In the presence of normal renal function, there are no differences between single- or multiple- dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1 ), nor is there any accumulation of metformin in either group at usual clinical doses.
The pharmacokinetics of GLUCOPHAGE XR in patients with type 2 diabetes are comparable to those in healthy normal adults.
Renal Impairment
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the CONTRAINDICATIONS, ADMINISTRATION ).
renal clearance is decreased WARNINGS, PRECAUTIONS,
(see Table and D
OSAGE
also see AND
Hepatic Impairment
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS).
Geriatrics
Limited data from controlled pharmacokinetic studies of GLUCOPHAGE in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged,
and C (^) max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1; also see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION ).
Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of GLUCOPHAGE
Subject Groups: GLUCOPHAGE dose a (number of subjects)
C (^) maxb (μg/mL)
T (^) maxc (hrs)
Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74)d 850 mg three times daily for 19 dosese^ (9)
1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42)
2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94)
600 (±132) 552 (±139) 642 (±173) Adults with type 2 diabetes: 8 50 mg single dose (23) 850 mg three times daily for 19 dosese^ (9)
1.48 (±0.5) 1.90 (±0.62)
3.32 (±1.08) 2.01 (±1.22)
491 (±138) 550 (±160)
Elderly f^ , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcrg^ 61-90 mL/min) (5) Moderate (CLcr 31-60 mL/min) (4) Severe (CLcr 10-30 mL/min) (6)
1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92)
3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10)
384 (±122) 108 (±57) 130 (±90) a (^) All doses given fasting except the first 18 doses of the multiple dose studies
b (^) Peak plasma concentration
c (^) Time to peak plasma concentration
d (^) Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
e (^) Kinetic study done following dose 19, given fasting
f (^) Elderly subjects, mean age 71 years (range 65-81 years)
g (^) CL 2 cr = creatinine clearance normalized to body surface area of 1.73 m
Pediatrics
After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean
metformin C (^) max and AUC differed less than 5% between pediatric type 2 diabetic patients
(12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
Gender
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16).
were made monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic
control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (up to 2500 mg/day) experienced
a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and
0.4%, respectively. The combination of GLUCOPHAGE and glyburide was effective in reducing
FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, –68 mg/dL, and –1.9%, respectively (see Table 3 ).
Table 3: Combined GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) or GLUCOPHAGE (GLU) Monotherapy: Summary of Mean Changes from Baseline in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)*
Comb (n=213)
Glyb (n=209)
GLU (n=210)
p-values Glyb vs Comb
GLU vs Comb
GLU vs Glyb Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 2 53.9 NS** NS** NS** Change at FINAL VISIT – 63.5 13.7 – 0.9 0.001 0.001 0.
Hemoglobin A (^) 1c (%) Baseline 8.8 8.5 8.9 NS** NS** 0. Change at FINAL VISIT – 1.7 0.2 – 0.4 0.001 0.001 0. Body Weight (lbs) Baseline 202.2 203. 0 204.0 NS** NS** NS** Change at FINAL VISIT 0.9 – 0.7 – 8.4 0.011 0.001 0.
- All patients on glyburide, 20 mg/day, at Baseline ** Not statistically significant
The magnitude of the decline in fasting blood glucose concentration following the institution of GLUCOPHAGE Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.
In clinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels, and had no adverse effects on other lipid levels (see Table 4 ).
Table 4: Summary of Mean Percent Change From Baseline of Major Serum Lipid Variables at Final Visit (29-week studies) GLUCOPHAGE vs Placebo
Combined GLUCOPHAGE/Glyburide vs Monotherapy GLUCOPHAGE (n=141)
Placebo (n=145)
GLUCOPHAGE (n=210)
GLUCOPHAGE/ Glyburide (n=213)
Glyburide (n=209) Total Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT
1%
1% Total Triglycerides (mg/dL) Baseline Mean % Change at FINAL VISIT
1%
4% LDL-Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT
1%
3% HDL-Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT
2%
5%
3%
1%
In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE tended to remain stable or even decrease somewhat (see Tables 2 and 3 ).
A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5 ). Patients randomized to receive
GLUCOPHAGE plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56%
reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was
achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, GLUCOPHAGE plus insulin versus insulin plus placebo, respectively, p=0.04.
A 16-week, double-blind, placebo-controlled, dose-response study of GLUCOPHAGE XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with
type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0% 11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.
Table 6: Summary of Mean Changes from Baseline in HbA1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) GLUCOPHAGE XR 500 mgOnce Placebo Daily*
1000 mg Once Daily
1500 mg Once Daily
2000 mg Once Daily
1000 mg Twice Daily
Hemoglobin A (^) 1c (%) Baseline Change at FINAL VISIT p-valuea
(n=115)
<0.
(n=115)
<0.
(n=111)
<0.
(n=125)
<0.
(n=112)
<0.
(n=111)
FPG (mg/dL) Baseline Change at FINAL VISIT p-value a
(n=126)
–15. <0.
(n=118)
–19. <0.
(n=120)
–28. <0.
(n=132)
–29. <0.
(n=122)
–33. <0.
(n=113)
Body Weight (lbs) Baseline Change at FINAL VISIT p-value a
(n=125)
–1. NS**
(n=119)
–1. NS**
(n=117)
–0. NS**
(n=131)
–1. NS**
(n=119)
–2. NS**
(n=113)
–1.
- All patients on diet therapy at Baseline a (^) All comparisons versus Placebo
** Not statistically significant
Compared with placebo, improvement in glycemic control was seen at all dose levels of GLUCOPHAGE XR Extended-Release Tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for GLUCOPHAGE and GLUCOPHAGE XR).
A 24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily with the evening meal, and GLUCOPHAGE Tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The GLUCOPHAGE dose had not necessarily been titrated to achieve a specific level of glycemic
control prior to study entry. Patients qualified for the study if HbA1c was ≤8.5% and FPG was
≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7.
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Table 7: Summary of Mean Changes from Baseline in HbA1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) GLUCOPHAGE 500 mg Twice Daily*
GLUCOPHAGE XR 1000 mg Once Daily
1500 mg Once Daily
Hemoglobin A (^) 1c (%) (n=67)^ (n=72)^ (n=66) Baseline 7.06 6.99 7. Change at 12 Weeks 0.14 0.23 0. (95% CI) (–0.03, 0.31) (0.10, 0.36) (–0.08, 0.15) Change at FINAL VISIT (^) 0.14 a^ 0.27 0. (95% CI) (–0.04, 0.31) (0.11, 0.43) (–0.02, 0.28) FPG (mg/dL) (n=69) (n=72) (n=70) Baseline 127.2 131.0 131. Change at 12 Weeks 12.9 9.5 3. (95% CI) (6.5, 19.4) (4.4, 14.6) (–0.4, 7.8) Change at FINAL VISIT 14.0 11.5 7. (95% CI) (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) Body Weight (lbs) (n=71) (n=74) (n=71) Baseline 210.3 202.8 192. Change at 12 Weeks 0.4 0.9 0. (95% CI) (–0.4, 1.5) (0.0, 2.0) (–0.4, 1.8) Change at FINAL VISIT 0.9 1.1 0. (95% CI) (–0.4, 2.2) (–0.2, 2.4) (–0.4, 2.0)
- All patients on GLUCOPHAGE 500 mg twice daily at Baseline a (^) n=
After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the
GLUCOPHAGE XR 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION ).
Changes in lipid parameters in the previously described placebo-controlled dose-response study of GLUCOPHAGE XR are shown in Table 8.
Table 9: Summary of Mean Percent Changes from Baseline in Major Lipid Variables at Final Visit (24-week study) GLUCOPHAGE GLUCOPHAGE XR 500 mg Twice Daily*
1000 mg Once Daily
1500 mg Once Daily Total Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT
(n=68)
0.1%
(n=70)
1.3%
(n=66)
0.1% Total Triglycerides (mg/dL) Baseline Mean % Change at FINAL VISIT
(n=68)
6.3%
(n=70)
25.3%
(n=66)
33.4% LDL-Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT
(n=68)
−1.3%
(n=70)
−3.3%
(n=66)
−3.7% HDL-Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT
(n=68)
4.8%
(n=70)
1.0%
(n=65)
–2.1%
- All patients on GLUCOPHAGE 500 mg twice daily at Baseline
Pediatric Clinical Studies
In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 10 ).
Table 10: GLUCOPHAGE vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline in Plasma Glucose and Body Weight at Final Visit GLUCOPHAGE Placebo p-Value FPG (mg/dL)* Baseline Change at FINAL VISIT
(n=37)
(n=36)
21.4 <0. Body Weight (lbs) Baseline Change at FINAL VISIT
(n=39)
(n=38)
- 2.0 NS** a (^) Pediatric patients mean age 13.8 years (range 10-16 years)
- All patients on diet therapy at Baseline ** Not statistically significant
INDICATIONS AND USAGE
GLUCOPHAGE (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
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GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
CONTRAINDICATIONS
GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m^2 ) (see WARNINGS and PRECAUTIONS ).
- Known hypersensitivity to metformin hydrochloride.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
WARNINGS
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 (see PRECAUTIONS).
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 (see DOSAGE AND ADMINISTRATION , CONTRAINDICATIONS , and PRECAUTIONS).
If metformin-associated lactic acidosis is suspected, immediately discontinue GLUCOPHAGE or GLUCOPHAGE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS).
o Before initiating GLUCOPHAGE or GLUCOPHAGE XR, obtain an estimated glomerular filtration rate (eGFR) o GLUCOPHAGE or GLUCOPHAGE XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m^2 (see CONTRAINDICATIONS). o Initiation of GLUCOPHAGE or GLUCOPHAGE XR is not recommended in patients with eGFR between 30-45 mL/min/1.73 m^2. o Obtain an eGFR at least annually in all patients taking GLUCOPHAGE or GLUCOPHAGE XR. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. o In patients taking GLUCOPHAGE or GLUCOPHAGE XR whose eGFR falls below 45 mL/min/1.73 m^2 , assess the benefit and risk of continuing therapy.
- Drug interactions —The concomitant use of GLUCOPHAGE or 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 or 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 m^2 ; 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 or 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 or 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 or GLUCOPHAGE XR.
- 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 GLUCOPHAGE or 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 and GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B 12 levels —In controlled clinical trials of GLUCOPHAGE of 29 weeks duration, a
decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical
manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to
interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of
GLUCOPHAGE or vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUCOPHAGE or GLUCOPHAGE XR and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests ).
Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to
be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum
vitamin B 12 measurements at 2- to 3-year intervals may be useful.
Hypoglycemia —Hypoglycemia does not occur in patients receiving GLUCOPHAGE or GLUCOPHAGE XR alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Laboratory Tests
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION ).
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with GLUCOPHAGE therapy, if
this is suspected, vitamin B 12 deficiency should be excluded.
Instruct patients to inform their doctor that they are taking GLUCOPHAGE or GLUCOPHAGE XR prior to any surgical or radiological procedure, as temporary discontinuation of GLUCOPHAGE or GLUCOPHAGE XR may be required until renal function has been confirmed to be normal (see PRECAUTIONS ).
Drug Interactions (Clinical Evaluation of Drug Interactions Conducted
with GLUCOPHAGE)
Glyburide —In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or
pharmacodynamics. Decreases in glyburide AUC and C (^) max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in Adult Patients ).
Furosemide —A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by
coadministration. Furosemide increased the metformin plasma and blood C (^) max by 22% and blood
AUC by 15%, without any significant change in metformin renal clearance. When administered
with metformin, the C (^) max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.
Nifedipine —A single-dose, metformin-nifedipine drug interaction study in normal healthy
volunteers demonstrated that coadministration of nifedipine increased plasma metformin C (^) max
and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T (^) max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Drugs that reduce metformin clearance —Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-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 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.
Other —Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving GLUCOPHAGE or GLUCOPHAGE XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUCOPHAGE or GLUCOPHAGE XR, the patient should be observed closely for hypoglycemia.
Carbonic anhydrase inhibitors —Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GLUCOPHAGE or GLUCOPHAGE XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
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