GLYBURIDE AND METFORMIN HYDROCHLORIDE tablet
Glyburide and Metformin Hydrochloride by
Drug Labeling and Warnings
Glyburide and Metformin Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by Aphena Pharma Solutions - Tennessee, Inc.. Drug facts, warnings, and ingredients follow.
Drug Details [pdf]
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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 494.00. 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 C4H11N5 ∙HCl and a molecular weight of 165.62. 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 tablets are 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: ammonio methacrylate copolymer (type B), croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium hydroxide, sorbic acid, titanium dioxide and triacetin. The 2.5 mg/500 mg tablet also contains: black iron oxide, D&C Yellow #10 Aluminum Lake, and yellow iron oxide. The 5 mg/500 mg tablet also contains: black iron oxide, FD&C Blue #2/Indigo Carmine Aluminum Lake, and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake.
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CLINICAL PHARMACOLOGY
Mechanism of Action
The Glyburide and Metformin Hydrochloride product combines glyburide and metformin hydrochloride, 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 HCl, 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® (Glyburide) 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 product 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 (1/400th 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 build-up 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 Renal Subject Groups: Metformin Cmaxb Tmaxc Clearance Dosea (number of subjects) (μg/mL) (hrs) (mL/min) aAll doses given fasting except the first 18 doses of the multiple-dose studies bPeak plasma concentration cTime to peak plasma concentration dSD = single dose eCombined results (average means) of five studies: mean age 32 years (range 23-59 years) fKinetic study done following dose 19, given fasting gElderly subjects, mean age 71 years (range 65-81 years) hCLcr = creatinine clearance normalized to body surface area of 1.73 m2 Healthy, nondiabetic Adults: 500 mg SDd (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg SD (74)e 1.60 (±0.38) 2.64(±0.82) 552 (±139) 850 mg t.i.d. for 19 dosesf (9) 2.01 (±0.42) 1.79(±0.94) 642 (±173) Adults with type 2 diabetes: 850 mg SD (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg t.i.d. for 19 dosesf (9) 1.90 (±0.62) 2.01 (±1.22) 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 61-90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) Moderate (CLcr 31-60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) Severe (CLcr 10-30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) Pediatrics
After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed < 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:
Table 2: Placebo- and Active-Controlled Trial of Glyburide and Metformin Hydrochloride in Patients with inadequate Glycemic Control on Diet and Exercise Alone: Summary of Trial Data at 20 Weeks Glyburide and Glyburide and Metformin Metformin Glyburide Metformin Hydrochloride Hydrochloride 2.5 mg 500 mg 1.25 mg/250 mg 2.5 mg/500 mg Placebo Tablets Tablets Tablets Tablets ap<0.001 bp<0.05 cp=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 -1.26a -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% 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).
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 a sulfonylurea (eg, 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 in Patients with Inadequate Glycemic Control on Sulfonyurea Alone: Summary of Trial Data at 16 Weeks Glyburide and Glyburide and Metformin Metformin Glyburide Metformin Hydrochloride Hydrochloride 5 mg 500 mg 2.5 mg/500 mg 5 mg/500 mg Tablets Tablets Tablets Tablets ap<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 -1.69a -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% 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.
Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride 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 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 Rosiglitazone + + Glyburide and Metformin Glyburide and Metformin Hydrochloride Hydrochloride a Adjusted for the baseline mean difference b p<0.001 Mean Final Dose Glyburide and Metformin 10 mg/1992 mg 9.6 mg/1914 mg Hydrochloride Rosiglitazone 0 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% 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
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CONTRAINDICATIONS
Glyburide and Metformin Hydrochloride Tablets are contraindicated in patients with:
- Renal disease or renal dysfunction (eg., 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).
- Known hypersensitivity to metformin hydrochloride or glyburide.
- 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
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BOXED WARNING
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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. A combination of 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.)
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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 2 ½ 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.
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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 anti-diabetic drug.
Glyburide and Metformin Hydrochloride
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.
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 in 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 observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).
Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well controlled on metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Glyburide and Metformin Hydrochloride must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy
Hypoglycemia
Patients receiving Glyburide and Metformin Hydrochloride in combination with a thiazolidinedione may be at risk for hypoglycemia.
Information for Patients
Glyburide and Metformin Hydrochloride
Patients should be informed of the potential risks and benefits of Glyburide and Metformin Hydrochloride and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Glyburide and Metformin Hydrochloride immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Glyburide and Metformin Hydrochloride, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Glyburide and Metformin Hydrochloride. (See Patient Information Printed Below.)
Laboratory Tests
Periodic fasting blood glucose (FBG) and HbA1c measurements should be performed to monitor therapeutic response.
Initial and periodic monitoring of hematologic parameters (eg, 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 metformin therapy, if this is suspected, Vitamin B12 deficiency should be excluded.
Drug Interactions
Glyburide and Metformin Hydrochloride
Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose 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 Glyburide and Metformin Hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glyburide and Metformin Hydrochloride, the patient should be observed closely for hypoglycemia. 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 sulfonylureas, which are extensively bound to serum proteins.
Glyburide
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Glyburide and Metformin Hydrochloride, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Glyburide and Metformin Hydrochloride, the patient should be observed closely for loss of blood glucose control.
A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.
Metformin Hydrochloride
Furosemide
A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax 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 co-administered chronically.
Nifedipine
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Cationic drugs
Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. 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. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Glyburide and Metformin Hydrochloride and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with the combined products in Glyburide and Metformin Hydrochloride. The following data are based on findings in studies performed with the individual products.
Glyburide
Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily [MRHD] dose of 20 mg for the glyburide component of Glyburide and Metformin Hydrochloride based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a two-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors.
There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.
Metformin Hydrochloride
Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the MRHD dose of 2000 mg of the metformin component of Glyburide and Metformin Hydrochloride based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.
There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately three times the MRHD dose of the metformin component of Glyburide and Metformin Hydrochloride based on body surface area comparisons.
Pregnancy
Teratogenic Effects
Pregnancy category B
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Glyburide and Metformin Hydrochloride should not be used during pregnancy unless clearly needed. (See below.)
There are no adequate and well-controlled studies in pregnant women with Glyburide and Metformin Hydrochloride or its individual components. No animal studies have been conducted with the combined products in Glyburide and Metformin Hydrochloride. The following data are based on findings in studies performed with the individual products.
Glyburide
Reproduction studies were performed in rats and rabbits at doses up to 500 times the MRHD dose of 20 mg of the glyburide component of Glyburide and Metformin Hydrochloride based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to glyburide.
Metformin hydrochloride
Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg of the metformin component of Glyburide and Metformin Hydrochloride based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Nonteratogenic Effects
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that Glyburide and Metformin Hydrochloride be used during pregnancy. However, if it is used, Glyburide and Metformin Hydrochloride should be discontinued at least two weeks before the expected delivery date. (See Pregnancy: Teratogenic Effects: Pregnancy Category B.)
Nursing Mothers
Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue Glyburide and Metformin Hydrochloride, taking into account the importance of the drug to the mother. If Glyburide and Metformin Hydrochloride is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Pediatric Use
The safety and efficacy of Glyburide and Metformin Hydrochloride was evaluated in an active-controlled, double-blind, 26-week randomized trial involving a total of 167 pediatric patients (ranging from 9 to 16 years of age) with type 2 diabetes. Glyburide and Metformin Hydrochloride was not shown statistically to be superior to either metformin or glyburide with respect to reducing HbA1c from baseline (see Table 5). No unexpected safety findings were associated with Glyburide and Metformin Hydrochloride in this trial.
Glyburide and Metformin Glyburide Metformin Hydrochloride 2.5 mg 500 mg 1.25 mg/250 mg Tablets Tablets Tablets Table 5: HbA1c (Percent) Change From Baseline at 26 Weeks: Pediatric Study Mean Final Dose 6.5 mg 1500 mg 3.1 mg/623 mg Hemoglobin A1c N=49 N=54 N=57 Baseline Mean (%) 7.70 7.99 7.85 Mean Change from Baseline -0.96 -0.48 -0.80 Difference from Metformin -0.32 Difference from Glyburide +0.16 Geriatric Use
Of the 642 patients who received Glyburide and Metformin Hydrochloride in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received Glyburide and Metformin Hydrochloride in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Glyburide and Metformin Hydrochloride should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, Glyburide and Metformin Hydrochloride should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Glyburide and Metformin Hydrochloride (see also WARNINGS and DOSAGE AND ADMINISTRATION).
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ADVERSE REACTIONS
Glyburide and Metformin Hydrochloride
In double-blind clinical trials involving Glyburide and Metformin Hydrochloride as initial therapy or as second-line therapy, a total of 642 patients received the combination product Glyburide and Metformin Hydrochloride, 312 received metformin therapy, 324 received glyburide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Glyburide and Metformin Hydrochloride (all strengths) as initial therapy and second-line therapy are listed in Table 6.
Table 6: Most Common Clinical Adverse Events (>5 %) in Double-Blind Clinical Studies of Glyburide and Metformin Hydrochloride Used as Initial or Second-Line Therapy Number (%) of Patients Glyburide and Metformin Adverse Event Placebo Glyburide Metformin Hydrochloride N=161 N=324 N=312 N=642 Upper respiratory infection 22 (13.7) 57 (17.6) 51 (16.3) 111 (17.3) Diarrhea 9 (5.6) 20 (6.2) 64 (20.5) 109 (17.0) Headache 17 (10.6) 37 (11.4) 29 (9.3) 57 (8.9) Nausea/vomiting 10 (6.2) 17 (5.2) 38 (12.2) 49 (7.6) Abdominal pain 6 (3.7) 10 (3.1) 25 (8.0) 44 (6.9) Dizziness 7 (4.3) 18 (5.6) 12 (3.8) 35 (5.5) In a controlled clinical trial of rosiglitazone versus placebo in patients treated with Glyburide and Metformin Hydrochloride (n=365), 181 patients received Glyburide and Metformin Hydrochloride with rosiglitazone and 184 received Glyburide and Metformin Hydrochloride with placebo.
Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184) of patients treated with placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated patients.
Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.
Hypoglycemia
In controlled clinical trials of Glyburide and Metformin Hydrochloride there were no hypoglycemic episodes requiring medical intervention and/or pharmacologic therapy; all events were managed by the patients. The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of Glyburide and Metformin Hydrochloride are summarized in Table 7. The frequency of hypoglycemic symptoms in patients treated with Glyburide and Metformin Hydrochloride 1.25 mg/250 mg was highest in patients with a baseline HbA1c <7%, lower in those with a baseline HbA1c of between 7% and 8%, and was comparable to placebo and metformin in those with a baseline HbA1c >8%. For patients with a baseline HbA1c between 8% and 11% treated with Glyburide and Metformin Hydrochloride 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with Glyburide and Metformin Hydrochloride experienced hypoglycemic symptoms. When rosiglitazone was added to Glyburide and Metformin Hydrochloride therapy, 22% of patients reported one or more fingerstick glucose measurements ≤50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were managed by the patients and only one patient discontinued for hypoglycemia. (See PRECAUTIONS: General: Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy.)
Gastrointestinal Reactions
The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7. Across all Glyburide and Metformin Hydrochloride trials, GI symptoms were the most common adverse events with Glyburide and Metformin Hydrochloride and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued Glyburide and Metformin Hydrochloride therapy due to GI adverse events.
Table 7: Treatment Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse Events in a Placebo- and Active-Controlled Trial of Glyburide and Metformin Hydrochloride as Initial Therapy Glyburide and Glyburide and Metformin Metformin Hydrochloride Hydrochloride Placebo Glyburide Metformin 1.25 mg/250 mg 2.5 mg/500 mg Variable Tablets Tablets Tablets Tablets N=161 N=160 N=159 N=158 N=162 Mean Final Dose 0 mg 5.3 mg 1317 mg 2.78 mg/557 mg 4.1 mg/824 mg Number (%) of patients with symptoms of hypoglycemia 5 (3.1) 34 (21.3) 5 (3.1) 18 (11.4) 61 (37.7) Number (%) of patients with gastrointestinal adverse events 39 (24.2) 38 (23.8) 69 (43.3) 50 (31.6) 62 (38.3) -
OVERDOSAGE
Glyburide
Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger.
Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.
Metformin Hydrochloride
Overdose of metformin hydrochloride has occurred, including ingestion of amounts > 50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
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DOSAGE AND ADMINISTRATION
General Considerations
Dosage of Glyburide and Metformin Hydrochloride must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glyburide/2000 mg metformin. Glyburide and Metformin Hydrochloride should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glyburide), to reduce GI side effects (largely due to metformin), and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.
With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to Glyburide and Metformin Hydrochloride and to identify the minimum effective dose for the patient. Thereafter, HbA1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone.
No studies have been performed specifically examining the safety and efficacy of switching to Glyburide and Metformin Hydrochloride therapy in patients taking concomitant glyburide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.
Glyburide and Metformin Hydrochloride in Patients with Inadequate Glycemic Control on Diet and Exercise
Recommended starting dose: 1.25 mg/250 mg once or twice daily with meals.
For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of Glyburide and Metformin Hydrochloride is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with baseline HbA1c >9% or an FPG >200 mg/dL, a starting dose of Glyburide and Metformin Hydrochloride 1.25 mg/250 mg twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg/250 mg per day every two weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of Glyburide and Metformin Hydrochloride as initial therapy, there was no experience with total daily doses greater than 10 mg/2000 mg per day. Glyburide and Metformin Hydrochloride 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.
Glyburide and Metformin Hydrochloride Use in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin
Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.
For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin alone, the recommended starting dose of Glyburide and Metformin Hydrochloride is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of Glyburide and Metformin Hydrochloride should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.
For patients previously treated with combination therapy of glyburide (or another sulfonylurea) plus metformin, if switched to Glyburide and Metformin Hydrochloride, the starting dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of Glyburide and Metformin Hydrochloride should be titrated as described above to achieve adequate control of blood glucose.
Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy
For patients not adequately controlled on Glyburide and Metformin Hydrochloride, a thiazolidinedione can be added to Glyburide and Metformin Hydrochloride therapy. When a thiazolidinedione is added to Glyburide and Metformin Hydrochloride therapy, the current dose of Glyburide and Metformin Hydrochloride can be continued and the thiazolidinedione initiated at its recommended starting dose. For patients needing additional glycemic control, the dose of the thiazolidinedione can be increased based on its recommended titration schedule. The increased glycemic control attainable with Glyburide and Metformin Hydrochloride plus a thiazolidinedione may increase the potential for hypoglycemia at any time of day.
In patients who develop hypoglycemia when receiving Glyburide and Metformin Hydrochloride and a thiazolidinedione, consideration should be given to reducing the dose of the glyburide component of Glyburide and Metformin Hydrochloride. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.
Specific Patient Populations
Glyburide and Metformin Hydrochloride is not recommended for use during pregnancy. The initial and maintenance dosing of Glyburide and Metformin Hydrochloride should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Glyburide and Metformin Hydrochloride to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly. (See WARNINGS.)
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HOW SUPPLIED
Repackaged by Aphena Pharma Solutions - TN.
See Repackaging Information for available configurations.
Glyburide and Metformin Hydrochloride Tablets, USP are available as follows:
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1.25 mg/250 mg —Each white to off-white, capsule-shaped, film coated tablet imprinted with
and 751 on one side and plain on the other side contains 1.25 mg of glyburide USP and 250 mg of metformin hydrochloride USP. Tablets are supplied in bottles of 100 (NDC: 0228-2751-11) with a child-resistant closure and bottles of 500 (NDC: 0228-2751-50) without a child-resistant closure.
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2.5 mg/500 mg —Each yellow, capsule-shaped, film coated tablet imprinted with
and 752 on one side and plain on the other side contains 2.5 mg of glyburide USP and 500 mg of metformin hydrochloride USP. Tablets are supplied in bottles of 100 (NDC: 0228-2752-11) with a child-resistant closure and bottles of 500 (NDC: 0228-2752-50) without a child-resistant closure.
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5 mg/500 mg — Each blue, capsule-shaped, film coated tablet imprinted with
and 753 on one side and plain on the other side contains 5 mg of glyburide USP and 500 mg of metformin hydrochloride USP. Tablets are supplied in bottles of 100 (NDC: 0228-2753-11) with a child-resistant closure and bottles of 500 (NDC: 0228-2753-50) without a child-resistant closure.
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Store at temperatures up to 25° C (77° F). [See USP Controlled Room Temperature.]
Dispense in a tight, light-resistant container as defined in the USP.
Manufactured by:
Actavis Elizabeth LLC
200 Elmora Avenue
Elizabeth, NJ 07207 USA
40-9070
Revised — March 2010
Micronase® is a registered trademark of Pharmacia & Upjohn Company.
Patient Package Insert
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PATIENT INFORMATION ABOUT GLYBURIDE (micronized) AND METFORMIN HYDROCHLORIDE TABLETS, USP
Revised – March 2010
WARNING: A small number of people who have taken metformin hydrochloride have developed a serious condition called lactic acidosis. Properly functioning kidneys are needed to help prevent lactic acidosis. Most people with kidney problems should not take Glyburide and Metformin Hydrochloride tablets. (See Question Nos. 9-13.)
Q1.Why do I need to take Glyburide and Metformin Hydrochloride?
Your doctor has prescribed Glyburide and Metformin Hydrochloride to treat your type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus.
Q2. What is type 2 diabetes?
People with diabetes are not able to make enough insulin and/or respond normally to the insulin their body does make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.
Q3. Whyis it important to control type 2 diabetes?
The main goal of treating diabetes is to lower your blood sugar to a normal level. Studies have shown that good control of blood sugar may prevent or delay complications such as heart disease, kidney disease, or blindness.
Q4. How is type 2 diabetes usually controlled?
High blood sugar can be lowered by diet and exercise, by a number of oral medications, and insulin injections. Before taking Glyburide and Metformin Hydrochloride you should first try to control your diabetes by exercise and weight loss. Even if you are taking Glyburide and Metformin Hydrochloride, you should still exercise and follow the diet recommended for your diabetes.
Q5.Does Glyburide and Metformin Hydrochloride work differently from other glucose-control medications?
Yes it does. The Glyburide and Metformin Hydrochloride product combines two glucose-lowering drugs, glyburide and metformin. These two drugs work together to improve the different metabolic defects found in type 2 diabetes. Glyburide lowers blood sugar primarily by causing more of the body’s own insulin to be released, and metformin lowers blood sugar, in part, by helping your body use your own insulin more effectively. Together, they are efficient in helping you achieve better glucose control.
Q6. What happens if my blood sugar is still too high?
When blood sugar cannot be lowered enough by Glyburide and Metformin Hydrochloride your doctor may prescribe injectable insulin or take other measures to control your diabetes.
Q7.Can Glyburide and Metformin Hydrochloride cause side effects?
Glyburide and Metformin Hydrochloride, like all blood sugar-lowering medications, can cause side effects in some patients. Most of these side effects are minor. However, there are also serious, but rare, side effects related to Glyburide and Metformin Hydrochloride (see Q9 - Q13).
Q8.What are the most common side effects of Glyburide and Metformin Hydrochloride?
The most common side effects of Glyburide and Metformin Hydrochloride are normally minor ones such as diarrhea, nausea, and upset stomach. If these side effects occur, they usually occur during the first few weeks of therapy. Taking your Glyburide and Metformin Hydrochloride with meals can help reduce these side effects.
Less frequently, symptoms of hypoglycemia (low blood sugar), such as lightheadedness, dizziness, shakiness, or hunger may occur. The risk of hypoglycemic symptoms increases when meals are skipped, too much alcohol is consumed, or heavy exercise occurs without enough food. Following the advice of your doctor can help you to avoid these symptoms.
Q9. Are there any serious side effects that Glyburide and Metformin Hydrochloride can cause?
People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take Glyburide and Metformin Hydrochloride may develop hemolytic anemia (fast breakdown of red blood cells). G6PD deficiency usually runs in families. Tell your doctor if you or any members of your family have been diagnosed with G6PD deficiency before you start taking Glyburide and Metformin Hydrochloride.
Glyburide and Metformin Hydrochloride rarely causes serious side effects. The most serious side effect that Glyburide and Metformin Hydrochloride can cause is called lactic acidosis.
Q10. What is lactic acidosis and can it happen to me?
Lactic acidosis is caused by a build-up of lactic acid in the blood. Lactic acidosis associated with metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.
It’s also important for your liver to be working normally when you take Glyburide and Metformin Hydrochloride. Your liver helps remove lactic acid from your bloodstream.
Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally.
There is no evidence that Glyburide and Metformin Hydrochloride causes harm to the kidneys or liver.
Q11. Are there other risk factors for lactic acidosis?
Your risk of developing lactic acidosis from taking Glyburide and Metformin Hydrochloride is very low as long as your kidneys and liver are healthy. However, some factors can increase your risk because they can affect kidney and liver function. You should discuss your risk with your doctor.
You should not take Glyburide and Metformin Hydrochloride if:
- You have chronic kidney or liver problems
- You have congestive heart failure which is treated with medications, eg,digoxin (Lanoxin®) or furosemide (Lasix®)
- You drink alcohol excessively (all the time or short-term “binge” drinking)
- You are seriously dehydrated (have lost a large amount of body fluids)
- You are going to have certain x-ray procedures with injectable contrast agents
- You are going to have surgery
- You develop a serious condition such as a heart attack, severe infection, or stroke
- You are ≥ 80 years of age and have NOT had your kidney function tested
Q12. What are the symptoms of lactic acidosis?
Some of the symptoms include: feeling very weak, tired or uncomfortable; unusual muscle pain, trouble breathing, unusual or unexpected stomach discomfort, feeling cold, feeling dizzy or lightheaded, or suddenly developing a slow or irregular heartbeat.
If you notice these symptoms, or if your medical condition has suddenly changed, stop taking Glyburide and Metformin Hydrochloride tablets and call your doctor right away. Lactic acidosis is a medical emergency that must be treated in a hospital.
Q13. What does my doctor need to know to decrease my risk of lactic acidosis?
Tell your doctor if you have an illness that results in severe vomiting, diarrhea, and/or fever, or if your intake of fluids is significantly reduced. These situations can lead to severe dehydration, and it may be necessary to stop taking Glyburide and Metformin Hydrochloride temporarily.
You should let your doctor know if you are going to have any surgery or specialized x-ray procedures that require injection of contrast agents. Glyburide and Metformin Hydrochloride therapy will need to be stopped temporarily in such instances.
Q14. Can I take Glyburide and Metformin Hydrochloride with other medications?
Remind your doctor that you are taking Glyburide and Metformin Hydrochloride when any new drug is prescribed or a change is made in how you take a drug already prescribed. Glyburide and Metformin Hydrochloride may interfere with the way some drugs work and some drugs may interfere with the action of Glyburide and Metformin Hydrochloride.
Q15. What if I become pregnant while taking Glyburide and Metformin Hydrochloride?
Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take Glyburide and Metformin Hydrochloride during pregnancy.
Usually your doctor will prescribe insulin while you are pregnant. As with all medications, you and your doctor should discuss the use of Glyburide and Metformin Hydrochloride if you are nursing a child.
Q16. How do I take Glyburide and Metformin Hydrochloride?
Your doctor will tell you how many Glyburide and Metformin Hydrochloride tablets to take and how often. This should also be printed on the label of your prescription. You will probably be started on a low dose of Glyburide and Metformin Hydrochloride and your dosage will be increased gradually until your blood sugar is controlled.
Q17.Where can I get more information about Glyburide and Metformin Hydrochloride?
This leaflet is a summary of the most important information about Glyburide and Metformin Hydrochloride. If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as Glyburide and Metformin Hydrochloride and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.Brands listed are the trademarks of their respective owners.
Manufactured by:
Actavis Elizabeth LLC
200 Elmora Avenue
Elizabeth, NJ 07207 USARevised – March 2010
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Repackaging Information
Please reference the How Supplied section listed above for a description of individual tablets or capsules. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:
Count 5/500mg 120 67544-511-70 360 67544-511-94 Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.
Repackaged by:
Cookeville, TN 38506
20120730KRW - PRINCIPAL DISPLAY PANEL - 5/500mg
- SPL UNCLASSIFIED SECTION
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INGREDIENTS AND APPEARANCE
GLYBURIDE AND METFORMIN HYDROCHLORIDE
glyburide and metformin hydrochloride tabletProduct Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC: 67544-511(NDC:0228-2753) Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength GLYBURIDE (UNII: SX6K58TVWC) (GLYBURIDE - UNII:SX6K58TVWC) GLYBURIDE 5 mg METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N) METFORMIN HYDROCHLORIDE 500 mg Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSES (UNII: 3NXW29V3WO) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYDEXTROSE (UNII: VH2XOU12IE) POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A) POVIDONE (UNII: FZ989GH94E) SODIUM HYDROXIDE (UNII: 55X04QC32I) SORBIC ACID (UNII: X045WJ989B) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C YELLOW NO. 6 (UNII: H77VEI93A8) METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577) FERROSOFERRIC OXIDE (UNII: XM0M87F357) Product Characteristics Color BLUE Score no score Shape OVAL (Capsule shaped) Size 16mm Flavor Imprint Code 753 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC: 67544-511-70 120 in 1 BOTTLE, PLASTIC 2 NDC: 67544-511-94 360 in 1 BOTTLE, PLASTIC Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076716 06/28/2005 Labeler - Aphena Pharma Solutions - Tennessee, Inc. (128385585) Establishment Name Address ID/FEI Business Operations Aphena Pharma Solutions - Tennessee, Inc. 128385585 Repack(67544-511)
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