Dosage Form: tablet, film coated
Glyburide and Metformin Hydrochloride Tablets, USP
1.25 mg/250 mg, 2.5 mg/500 mg, 5 mg/500 mg
Rx only
DESCRIPTION
Glyburide and Metformin hydrochloride tablets, USP contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, Glyburide and Metformin hydrochloride.
Glyburide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide is a white to off-white crystalline compound with a molecular formula of C23H28ClN3O5S and a molecular weight of 494.01. The structural formula is represented below.
Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound with a molecular formula of C4H12ClN5 (monohydrochloride) 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. The structural formula is as shown:
Glyburide and Metformin hydrochloride is available for oral administration in tablets containing 1.25 mg glyburide with 250 mg metformin hydrochloride, 2.5 mg glyburide with 500 mg metformin hydrochloride, and 5 mg glyburide with 500 mg metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol and titanium dioxide. The 1.25 mg/250 mg and 5 mg/500 mg tablets also contain D&C Yellow # 10 Aluminum Lake and FD&C Yellow # 6 Aluminum Lake; 2.5 mg/500 mg tablets contain FD&C Yellow # 6 Aluminum Lake as a color additive.
CLINICAL PHARMACOLOGY
Mechanism of Action
Glyburide and Metformin hydrochloride tablets contain two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Pharmacokinetics
Absorption and Bioavailability
Glyburide and Metformin Hydrochloride
In bioavailability studies of Glyburide and Metformin hydrochloride 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of the Micronase® brand of glyburide coadministered with metformin. The glyburide component of Glyburide and Metformin hydrochloride, therefore, is not bioequivalent to Micronase®. The metformin component of Glyburide and Metformin hydrochloride is bioequivalent to metformin coadministered with glyburide.
Following administration of a single Glyburide and Metformin hydrochloride 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Cmax and a relatively small effect of food on the AUC of the glyburide component. The Tmax for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.
Glyburide
Single-dose studies with Micronase® tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between Glyburide and Metformin hydrochloride and single-ingredient glyburide products.
Metformin hydrochloride
The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg 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 peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
Glyburide
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding results in fewer drug-drug interactions with glyburide tablets in clinical use.
Metformin Hydrochloride
The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism and Elimination
Glyburide
The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400 and 1⁄40 as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.
Metformin Hydrochloride
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been 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.
Special Populations
Patients with Type 2 Diabetes
Multiple-dose studies with glyburide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.
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.
Hepatic Insufficiency
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin.
Renal Insufficiency
No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.
In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1: also, see WARNINGS).
Geriatrics
There is no information on the pharmacokinetics of glyburide in elderly patients.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, when 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). Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
| Subject Groups: Metformin Dosea (number of subjects) | Cmaxb (µg/mL) | Tmaxc (hrs) | Renal Clearance (mL/min) | |
|---|---|---|---|---|
| Healthy, nondiabetic adults: 500 mg SDd(24) 850 mg SD (74)e 850 mg t.i.d. for 19 dosesf (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: 850 mg SD (23) 850 mg t.i.d. for 19 doses f(9) | 1.48 (±0.5) 1.90 (±0.62) | 3.32 (±1.08) 2.01 (±1.22) | 491 (±138) 550 (±160) | |
| Elderlyg healthy nondiabetic adults: 850 mg SD (12) | 2.45 (±0.70) | 2.71 (±1.05) | 412 (±98) | |
| Renal-impaired adults: 850 mg SD Mild (CLcrh 61 to 90 mL/min) (5) Moderate (CLcr 31 to 60 mL/min) (4) Severe (CLcr 10 to 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 SD = single dose
e Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)
f Kinetic study done following dose 19, given fasting
g Elderly subjects, mean age 71 years (range 65 to 81 years)
h CLcr = creatinine clearance normalized to body surface area of 1.73 m2
Pediatrics
After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight- matched healthy adults (20 to 45 years of age), all with normal renal function.
After administration of a single oral Glyburide and Metformin hydrochloride tablet with food, dose-normalized geometric mean glyburide Cmax and AUC in pediatric patients with type 2 diabetes (11 to 16 years of age, n=28, mean body weight of 97 kg) differed <6% from historical values in healthy adults.
Gender
There is no information on the effect of gender on the pharmacokinetics of glyburide.
Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Race
No information is available on race differences in the pharmacokinetics of glyburide.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Clinical Studies
Patients with Inadequate Glycemic Control on Diet and Exercise Alone
In a 20-week, double-blind, multicenter U.S. clinical trial, a total of 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (baseline fasting plasma glucose [FPG] < 240 mg/dL, baseline hemoglobin A1c [HbA1c] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin, Glyburide and Metformin hydrochloride 1.25 mg/250 mg, or Glyburide and Metformin hydrochloride 2.5 mg/500 mg. After four weeks, the dose was progressively increased (up to the eight-week visit) to a maximum of four tablets daily as needed to reach a target FPG of 126 mg/dL. Trial data at 20 weeks are summarized in Table 2.
| Placebo | Glyburide 2.5 mg tablets | Metformin 500 mg tablets | Glyburide and Metformin Hydrochloride 1.25 mg/250 mg tablets | Glyburide and Metformin Hydrochloride 2.5 mg/500 mg tablets | |
| Mean Final Dose | 0 mg | 5.3 mg | 1317 mg | 2.78 mg/557 mg | 4.1 mg/824 mg |
| Hemoglobin A1c | N = 147 | N = 142 | N = 141 | N = 149 | N = 152 |
| Baseline Mean (%) | 8.14 | 8.14 | 8.23 | 8.22 | 8.20 |
| Mean Change from Baseline | -0.21 | -1.24 | -1.03 | -1.48 | -1.53 |
| Difference from Placebo | -1.02 | -0.82 | -1.26a | -1.31a | |
| Difference from Glyburide | -0.24b | -0.29b | |||
| Difference from Metformin | -0.44b | -0.49b | |||
| Fasting Plasma Glucose | N = 159 | N = 158 | N = 156 | N = 153 | N = 154 |
| Baseline Mean FPG (mg/dL) | 177.2 | 178.9 | 175.1 | 178 | 176.6 |
| Mean Change from Baseline | 4.6 | -35.7 | -21.2 | -41.5 | -40.1 |
| Difference from Placebo | -40.3 | -25.8 | -46.1a | -44.7a | |
| Difference from Glyburide | -5.8c | -4.5c | |||
| Difference from Metformin | -20.3c | -18.9c | |||
| Body Weight Mean Change from Baseline | -0.7 kg | +1.7 kg | -0.6 kg | +1.4 kg | +1.9 kg |
| Final HbA1c Distribution (%) | N = 147 | N = 142 | N = 141 | N = 149 | N = 152 |
| <7% | 19.7% | 59.9% | 50.4% | 66.4% | 71.7% |
| ≥7% and <8% | 37.4% | 26.1% | 29.8% | 25.5% | 19.1% |
| ≥8% | 42.9% | 14.1% | 19.9% | 8.1% | 9.2% |
a p<0.001
b p<0.05
c p = NS
Treatment with Glyburide and Metformin hydrochloride resulted in significantly greater reduction in HbA1c and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, Glyburide and Metformin hydrochloride therapy resulted in greater reduction in FPG compared to glyburide, metformin, or placebo, but the differences from Glyburide and Metformin did not reach statistical significance.
Changes in the lipid profile associated with Glyburide and Metformin hydrochloride treatment were similar to those seen with glyburide, metformin, and placebo.
The double-blind, placebo-controlled trial described above restricted enrollment to patients with HbA1c <11% or FPG < 240 mg/dL. Screened patients ineligible for the first trial because of HbA1c and/or FPG exceeding these limits were treated directly with Glyburide and Metformin hydrochloride 2.5 mg/500 mg in an open-label, uncontrolled protocol. In this study, 3 out of 173 patients (1.7%) discontinued because of inadequate therapeutic response.
Across the group of 144 patients who completed 26 weeks of treatment, mean HbA1c was reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/dL and reduced to 164 and 161 mg/dL after 2 and 26 weeks, respectively. The mean final titrated dose of Glyburide and Metformin hydrochloride was 7.85 mg/1569 mg (equivalent to approximately three Glyburide and Metformin hydrochloride 2.5 mg/500 mg tablets per day).
Patients with Inadequate Glycemic Control on Sulfonylurea Alone
In a 16-week, double-blind, active-controlled U.S. clinical trial, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA1c 9.5%, mean baseline FPG 213 mg/dL) while being treated with at least one-half the maximum dose of sulfonylurea (e.g. glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin (500 mg), Glyburide and Metformin hydrochloride 2.5 mg/500 mg, or Glyburide and Metformin hydrochloride 5 mg/500 mg. The doses of metformin and Glyburide and Metformin hydrochloride were titrated to a maximum of four tablets daily as needed to achieve FPG < 140 mg/dL. Trial data at 16 weeks are summarized in Table 3.
Glyburide 5 mg tablets | Metformin 500 mg tablets | Glyburide and Metformin Hydrochloride 2.5 mg/500 mg tablets | Glyburide and Metformin Hydrochloride 5 mg/500 mg tablets | |
| Mean Final Dose | 20 mg | 1840 mg | 8.8 mg/1760 mg | 17 mg/1740 mg |
| Hemoglobin A1c | N = 158 | N = 142 | N = 154 | N = 159 |
| Baseline Mean (%) | 9.63 | 9.51 | 9.43 | 9.44 |
| Final Mean | 9.61 | 9.82 | 7.92 | 7.91 |
| Difference from Glyburide | -1.69a | -1.70a | ||
| Difference from Metformin | -1.90a | -1.91a | ||
| Fasting Plasma Glucose | N = 163 | N = 152 | N = 160 | N = 160 |
| Baseline Mean (mg/dL) | 218.4 | 213.4 | 212.2 | 210.2 |
| Final Mean | 221.0 | 233.8 | 169.6 | 161.1 |
| Difference from Glyburide | -51.3a | -59.9a | ||
| Difference from Metformin | -64.2a | -72.7a | ||
| Body Weight Mean Change from Baseline | +0.43 kg | -2.76 kg | +0.75 kg | +0.47 kg |
| Final HbA1c Distribution (%) | N = 158 | N = 142 | N = 154 | N=159 |
| <7% | 2.5% | 2.8% | 24.7% | 22.6% |
| ≥7% and <8% | 9.5% | 11.3% | 33.1% | 37.1% |
| ≥8% | 88% | 85.9% | 42.2% | 40.3% |
a p<0.001
After 16 weeks, there was no significant change in the mean HbA1c in patients randomized to glyburide or metformin therapy. Treatment with Glyburide and Metformin hydrochloride at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbA1c, FPG, and PPG from baseline compared to glyburide or metformin alone.
Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Tablet Therapy.
In a 24-week, double-blind, multicenter U.S. clinical trial, patients with type 2 diabetes not adequately controlled on current oral antihyperglycemic therapy (either monotherapy or combination therapy) were first switched to open label Glyburide and Metformin hydrochloride 2.5 mg/500 mg tablets and titrated to a maximum daily dose of 10 mg/2000 mg. A total of 365 patients inadequately controlled (HbA1c >7.0% and ≤10%) after 10 to 12 weeks of a daily Glyburide and Metformin hydrochloride dose of at least 7.5 mg/1500 mg were randomized to receive add-on therapy with rosiglitazone 4 mg or placebo once daily. After eight weeks, the rosiglitazone dose was increased to a maximum of 8 mg daily as needed to reach a target mean daily glucose of 126 mg/dL or HbA1c <7%. Trial data at 24 weeks or the last prior visit are summarized in Table 4.
| Placebo + Glyburide and Metformin Hydrochloride | Rosiglitazone + Glyburide and Metformin Hydrochloride | |
| Mean Final Dose Glyburide and metformin hydrochloride Rosiglitazone | 10 mg/1992 mg 0 mg | 9.6 mg/1914 mg 7.4 mg |
| Hemoglobin A1c | N=178 | N=177 |
| Baseline Mean (%) | 8.09 | 8.14 |
| Final Mean | 8.21 | 7.23 |
| Difference from Placeboa | -1.02b | |
| Fasting Plasma Glucose | N=181 | N=176 |
| Baseline Mean (mg/dL) | 173.1 | 178.4 |
| Final Mean | 181.4 | 136.3 |
| Difference from Placeboa | -48.5b | |
| Body Weight Mean Change from Baseline | +0.03 kg | +3.03 kg |
| Final HbA1c Distribution (%) | N=178 | N=177 |
| <7% | 13.5% | 42.4% |
| ≥7% and <8% | 32.0% | 38.4% |
| ≥8% | 54.5% | 19.2% |
a Adjusted for the baseline mean diffrence
b p<0.001
For patients who did not achieve adequate glycemic control on Glyburide and Metformin hydrochloride, the addition of rosiglitazone, compared to placebo, resulted in significant lowering of HbA1c and FPG.
INDICATIONS AND USAGE
Glyburide and Metformin hydrochloride tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
CONTRAINDICATIONS
Glyburide and Metformin hydrochloride is contraindicated in patients with:
1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
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.
Glyburide and Metformin hydrochloride should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)
WARNINGS
Metformin Hydrochloride
Lactic acidosis:
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Glyburide and Metformin hydrochloride tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glyburide and Metformin hydrochloride treatment should not be initiated in patients > 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Glyburide and Metformin hydrochloride should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Glyburide and Metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Glyburide and Metformin hydrochloride, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Glyburide and Metformin hydrochloride should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Glyburide and Metformin hydrochloride should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Glyburide and Metformin hydrochloride, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Glyburide and Metformin hydrochloride do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Glyburide and Metformin hydrochloride, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY
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 trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g 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.
PRECAUTIONS
General
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glyburide and Metformin hydrochloride or any other antidiabetic drug.
Glyburide and Metformin Hydrochloride
Hypoglycemia
Glyburide and Metformin hydrochloride is capable of producing hypoglycemia or hypoglycemic symptoms, therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal or hepatic insufficiency may cause elevated drug levels of both Glyburide and Metformin hydrochloride, and the hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and people who are taking beta-adrenergic blocking drugs.
Glyburide
Hemolytic anemia
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glyburide and Metformin hydrochloride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
Metformin Hydrochloride
Monitoring of renal function
Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Glyburide and Metformin hydrochloride. In patients with advanced age, Glyburide and Metformin hydrochloride should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Glyburide and Metformin hydrochloride should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of Glyburide and Metformin hydrochloride therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Glyburide and Metformin hydrochloride discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition
Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Glyburide and Metformin hydrochloride should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
Hypoxic states
Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Glyburide and Metformin hydrochloride therapy, the drug should be promptly discontinued.
Surgical procedures
Glyburide and Metformin hydrochloride therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.
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 Glyburide and Metformin hydrochloride. Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of hypoglycemia.
Impaired hepatic function
Since impaired hepatic function has been associated with some cases of lactic acidosis, Glyburide and Metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels
In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12, without clinical manifestations, was
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