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All about: Glyburide and Metformin

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Generic Name: Glyburide and Metformin Hydrochloride
Dosage Form: Tablets

Glyburide and Metformin Description

Glyburide and Metformin hydrochloride tablets 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-[[ρ-[2-(5-chloro-ο-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 in combination 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.

Colors: 1.25 mg/250 mg and 5 mg/500 mg tablets 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.

Glyburide and Metformin - 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 combination and single ingredient glyburide products.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50-60%. 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 24-48 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 (1/400th and 1/40th 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, 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.

Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters
Following Single or Multiple Oral Doses of Metformin
Subject Groups: Metformin
Dose* (number of subjects)
Cmax
(µg/mL)
Tmax
(hrs)
Renal 
Clearance
(mL/min)
*
All doses given fasting except the first 18 doses of the multiple-dose studies
Peak plasma concentration
Time to peak plasma concentration
§
SD=single dose
Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
#
Kinetic study done following dose 19, given fasting
Þ
Elderly subjects, mean age 71 years (range 65-81 years)
ß
CLcr = creatinine clearance normalized to body surface area of 1.73 m2
Healthy, nondiabetic adults:
500 mg SD§(24)
850 mg SD (74)
850 mg t.i.d. for 19 doses# (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 #(9)
1.48 (±0.5)
1.90 (±0.62)
3.32 (±1.08)
2.01 (±1.22)
491 (±138)
550 (±160)
ElderlyÞ healthy nondiabetic adults:
850 mg SD (12)
2.45 (±0.70) 2.71 (±1.05) 412 (±98)
Renal-impaired adults: 850 mg SD
Mild (CLcrß 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)

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.

Pharmacokinetics information for pediatric patients is approved for Bristol-Myers Squibb Company's Glyburide and Metformin HCl tablets. However, due to Bristol-Myers Squibb's marketing exclusivity rights, this product is not labeled with pediatric pharmacokinetic information.

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 patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies

Initial Therapy

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.

Table 2: Placebo- and Active-Controlled Trial of Glyburide and
Metformin Hydrochloride as Initial Therapy: Summary of Trial
Data at 20 Weeks
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
*
p<0.001
p<0.05
p = NS
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 -1.26* -1.31*
Difference from
Glyburide
-0.24 -0.29
Difference from
Metformin
-0.44 -0.49
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 -46.1* -44.7*
Difference from
Glyburide
-5.8 -4.5
Difference from
Metformin
-20.3 -18.9
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%

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, three 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 was 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).

Second Line Therapy

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.

Table 3: Glyburide and Metformin Hydrochloride as Second-
Line Therapy: Summary of Trial Data at 16 Weeks
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
*
p<0.001
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 -1.69* -1.70*
Difference from Metformin -1.90* -1.91*
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 -51.3* -59.9*
Difference from Metformin -64.2* -72.7*
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%

After 16 weeks, there was no significant change in the mean HbA1c in patients randomized to glyburide or to 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.

In a 24-week, double-blind, multi-center 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 at the last prior visit are summarized in Table 4.

Table 4: Effects of Adding Rosiglitazone or Placebo in Patients Treated
with Glyburide and Metformin Hydrochloride in a 24-Week Trial
Placebo
+
Glyburide and Metformin
hydrochloride
Rosiglitazone
+
Glyburide and Metformin
hydrochloride
*
Adjusted for the baseline mean difference
p < 0.001
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 Placebo* -1.02
Fasting Plasma Glucose N=181 N=176
Baseline Mean (mg/dL) 173.1 178.4
Final Mean 181.4 136.3
Difference from Placebo* -48.5
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%

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 for Glyburide and Metformin

Glyburide and Metformin hydrochloride tablets are indicated as initial therapy, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone.

Glyburide and Metformin hydrochloride tablets are indicated as second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes. For patients requiring additional therapy, a thiazolidinedione may be added to Glyburide and Metformin hydrochloride tablets to achieve additional glycemic control.

Contraindications

Glyburide and Metformin hydrochloride tablets are 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. Congestive heart failure requiring pharmacologic treatment.
  3. Known hypersensitivity to metformin hydrochloride or glyburide.
  4. 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; 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). 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 the 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 maybe 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

The glyburide component of Glyburide and Metformin HCl tablets is not bioequivalent to Micronase®. In addition, it has been reported that bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentration that are not bioequivalent to those from nonmicronized glyburide tablets 5 mg. Therefore, patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents.

General

Glyburide and Metformin Hydrochloride

Hypoglycemia

Glyburide and Metformin hydrochloride tablets are 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 duri

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Some commonly used brand names are: In the U.S.— Purinethol In Canada— Purinethol Another commonly used name is 6-MP . Category Antineoplastic Immunosuppressant Description Mercaptopurine (mer-kap-toe-PYOOR-een) belongs to the group of medicines known as antimetabolites. more...

Mesantoin Mesantoin
Generic Name: mephenytoin (meh FEN i toyn) Brand Names: Mesantoin What is Mesantoin (mephenytoin)? Mephenytoin is a drug used to control seizures. It works by slowing down impulses in the brain that cause seizures. Mephenytoin is usually reserved for seizure conditions that have not res more...