Glyburide-Metformin (glyburide/metformin HCl)

Glyburide is a sulfonylurea antidiabetic agent.

Metformin hydrochloride is a biguanide antidiabetic agent.

The precise mechanism(s) of hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established, but the drugs, including glyburide, initially appear to lower blood glucose concentration principally by stimulating secretion of endogenous insulin from the beta cells of the pancreas. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin. Other mechanisms of the hypoglycemic action associated with short-term glyburide therapy appear to include reduction of basal hepatic glucose production and enhancement of peripheral insulin action at postreceptor (probably intracellular) site(s).

Following short-term administration of glyburide, an increase in insulin binding has been demonstrated in monocytes obtained from healthy individuals, but not in adipocytes obtained from diabetic patients. Like other sulfonylureas, glyburide alone is ineffective in the absence of functioning beta cells. On a weight basis, glyburide is one of the most potent of the sulfonylurea antidiabetic agents; although an exact dosage relationship does not exist, a daily glyburide dosage of 5 mg controls blood glucose concentration to approximately the same degree as daily dosages of glipizide 5-10 mg.

The mechanism(s) of action of glyburide during prolonged administration has not been fully established. Glyburide-induced improvement in glucose tolerance during long-term therapy persists despite a gradual decline in glucose- or meal-stimulated secretion of endogenous insulin towards pretreatment levels. During prolonged administration of sulfonylureas, including glyburide, extrapancreatic effects appear to substantially contribute to the hypoglycemic action of the drugs.

Many extrapancreatic effects of the drugs have been proposed and/or studied, but the principal effects appear to include enhanced peripheral sensitivity to insulin and reduction of basal hepatic glucose production; however, the nature of the long-term hypoglycemic effect and the mechanism(s) involved remain to be fully elucidated. There is evidence that glyburide enhances the peripheral action of insulin at postreceptor (probably intracellular) site(s) and reduces basal hepatic glucose production during long-term administration. An increase in insulin binding and/or number of insulin receptors has also been demonstrated in monocytes and adipocytes obtained from diabetic patients receiving long-term therapy with the drug.

Glyburide produces a mild diuresis by enhancing renal free water clearance. The diuretic effect has been demonstrated in healthy individuals, diabetic patients, and patients with neurohypophyseal diabetes insipidus; the drug apparently has no diuretic effect in patients with nephrogenic diabetes insipidus. The exact mechanism by which glyburide enhances renal free water clearance is not known.

The diuretic action apparently is not mediated through an effect on the release of vasopressin (antidiuretic hormone) from the posterior pituitary or on the action of vasopressin at the renal collecting ducts. It has been suggested that glyburide inhibits reabsorption of sodium in the proximal renal tubule or nonvasopressin-dependent reabsorption of water in the distal renal tubule.

Currently available tablet formulations of glyburide appear to be reliably and almost completely absorbed following oral administration. Bioavailability studies have demonstrated that micronized glyburide and nonmicronized (conventional) glyburide tablets are not bioequivalent; therefore, patients switching from micronized to nonmicronized tablets or vice versa should have their dosage retitrated. Food apparently does not affect the rate or extent of absorption of glyburide.

Following oral administration of a single 5-mg dose of glyburide, the drug appears in plasma or serum within 15-60 minutes and peak plasma concentrations are attained within 2-4 hours (range: 2-8 hours). The AUC for glyburide increases in proportion to increasing doses. Substantial interindividual variations in steady-state serum concentration have been reported in diabetic patients receiving the same dosage of glyburide.

Following single oral doses of glyburide in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 15-60 minutes and is maximal within 1-2 hours; in diabetic patients, increases in plasma insulin concentration may persist for up to 24 hours. Following single oral doses of the drug in fasting healthy individuals, the degree and duration of lowering of blood glucose concentration are proportional to the dose administered and the AUC; the hypoglycemic action generally begins within 45-60 minutes and is maximal within 1.5-3 hours. In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of glyburide may persist for up to 24 hours.

Distribution of glyburide into human body tissues and fluids has not been fully characterized. Following oral or IV administration in animals, highest concentrations of the drug are attained in the liver, kidneys, and small and large intestines, with lower concentrations in the stomach, pancreas, spleen, mesenteric lymph nodes, mesenteric and retroperitoneal fat, heart, lungs, gonads, skeletal muscle, and brain. In humans, glyburide is distributed in substantial amounts into bile.

Glyburide appears to cross the placenta, since prolonged hypoglycemia has occurred in neonates born to women who received the drug up to the time of delivery. It is not known if the drug is distributed into human milk. Glyburide is more than 99% bound to serum proteins and its major metabolite, 4-trans-hydroxyglyburide, is more than 97% bound to serum proteins.

Glyburide has a higher affinity for binding to serum albumin than does glipizide. The protein binding of glyburide is principally nonionic; consequently, glyburide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature.

Serum concentrations of glyburide appear to decline in a biphasic manner. In studies in healthy adults using assays relatively specific for unchanged glyburide, the terminal elimination half-life has reportedly averaged 1.4-1.8 hours (range: 0.7-3 hours); when assays that also measured metabolites of the drug were used, the terminal elimination half-life has averaged about 10 hours (range: 5-26 hours). Serum glyburide concentrations may be increased in patients with renal or hepatic insufficiency.

Data are limited, but the half-life may be prolonged in patients with severe renal impairment. In one study in patients with normal hepatic function and impaired renal function given a single oral dose of radiolabeled glyburide, the plasma half-life of total radioactivity was 2-5 hours in those with creatinine clearances of 29-131 mL/minute per 1.73 m2 and 11 hours in one patient with a creatinine clearance of 5 mL/minute per 1.73 m2; in those patients with creatinine clearances of 29-131 mL/minute per 1.73 m2, no relationship between plasma half-life and creatinine clearance was observed.

Glyburide appears to be completely metabolized, probably in the liver. The drug is metabolized at the cyclohexyl ring principally to-hydroxyglyburidetrans4-; the 4-trans-hydroxy metabolite has only 0.25% of the hypoglycemic activity of glyburide following oral administration in rabbits, but has about 15% of the hypoglycemic activity of the parent compound following intraperitoneal administration in rats. Glyburide is also metabolized to the 3-cis-hydroxy derivative and to another unidentified metabolite; the 3-cis-hydroxy metabolite has 2.5% of the hypoglycemic activity of glyburide following oral administration in rabbits.

The hypoglycemic activity of glyburide metabolites is generally considered clinically unimportant; however, results of studies in rats indicate that retention of the 4-trans-hydroxy metabolite in the presence of renal insufficiency may enhance and prolong the hypoglycemic effect of the drug.

Unlike other currently available sulfonylurea antidiabetic agents which are excreted principally in urine, glyburide is excreted as metabolites in urine and feces in approximately equal proportions. Fecal excretion appears to occur almost completely via biliary elimination; only small amounts may be excreted in feces as unabsorbed drug following oral administration. Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug.

Following oral administration of a single 5-mg dose of glyburide in healthy individuals, approximately 30-50% of the dose is excreted in urine as metabolites within 24 hours; about 80% of the urinary excretion occurs as the 4-trans-hydroxy metabolite, 15% as the 3-cis-hydroxy metabolite, and 5% as an unidentified metabolite. Fecal excretion occurs more slowly, but a single oral dose of the drug is completely excreted in urine and feces within 3-5 days in healthy individuals.

The effects of renal impairment on the elimination of glyburide and its metabolites have not been fully evaluated. Limited data indicate that renal excretion of glyburide metabolites and plasma clearance of glyburide may be substantially decreased in patients with severe renal impairment. Glyburide appears to be only minimally removed by hemodialysis.

Metformin a biguanide antidiabetic agent, lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus. Biguanides usually do not produce hypoglycemia in patients with diabetes and do not affect normal blood glucose concentrations in nondiabetic individuals; metformin, even in excessive dosage, normally does not lower glucose concentrations below euglycemia, although hypoglycemia occasionally may occur with overdosage. Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the medication improves both peripheral and hepatic sensitivity to insulin.

Improved insulin sensitivity occurs principally as a result of decreased hepatic glucose production and enhanced insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes); the relative contribution of these mechanisms to the antihyperglycemic effect of metformin has not been fully elucidated. The apparent improvement in peripheral glucose disposal with metformin therapy has been attributed principally to improved metabolism of glucose via nonoxidative (anaerobic) pathways (e.g., glycogen formation in skeletal muscle, postprandial lactate production in splanchnic tissues, lipogenesis in adipose tissue). Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations.

Although some investigators have suggested that reduction of hepatic glucose production may be the medication's principal antihyperglycemic mechanism, this effect has not been demonstrated in all studies. In vitro studies in hepatocytes indicate that metformin, at concentrations similar to or higher than those observed with therapeutic dosages, enhances insulin-induced suppression of gluconeogenesis and decreases glucagon-stimulated gluconeogenesis. Insulin secretion usually remains unchanged during metformin therapy; fasting insulin concentrations and day-long plasma insulin response remain the same or may even decrease.

The magnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia. Metformin also may decrease plasma glucose concentrations by enhancing basal glucose disposal through insulin-independent mechanisms (e.g., a decrease in free fatty acid oxidation), but such effects appear to be modest.

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours. The absolute oral bioavailability of the medication under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g; binding of the medication to the intestinal wall may explain the difference between the amount of medication absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies. In single-dose studies with metformin hydrochloride immediate-release tablets at doses of 0.5-1.5 g or 0.85-2.55 g, plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process.

Food decreases and slightly delays the absorption of metformin immediate-release tablets; the clinical importance of these effects is unknown. Administration of metformin hydrochloride immediate-release tablets with food reportedly has decreased peak plasma concentrations of the medication by 35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%, and delayed time to peak plasma concentration by 35-40 minutes compared with these parameters in fasting individuals receiving this metformin preparation. However, in one study, concomitant administration of the medication as immediate-release tablets with food had a less pronounced effect (average reduction in bioavailability of 10%) on absorption.

Following oral administration of metformin hydrochloride as an extended-release tablet preparation with food, the extent of absorption (as measured by AUC) increased by approximately 50%, but peak plasma concentrations and time to achieve peak plasma concentrations were not altered. However, following administration of another metformin hydrochloride extended-release preparation (Glumetza(R)) with low-fat and high-fat meals, the AUCs increased by 38 and 73%, respectively, compared with those in the fasting state. Following oral administration of metformin hydrochloride as an immediate-release oral solution with food, the extent of absorption (as measured by AUC) increased by approximately 17-21% compared with administration in the fasted state.

Food delayed the time to achieve peak plasma concentrations by 1.4 hours compared with administration in the fasted state. The pharmacokinetics of immediate-release metformin oral solution were not appreciably affected by the fat content of meals. Following administration of a single 500-mg dose of metformin hydrochloride as immediate-release tablets with food in pediatric patients (12-16 years of age) with type 2 diabetes mellitus, mean peak plasma concentrations and AUC differed less than 5% compared with those values in healthy adults; all patients had normal renal function.

In pediatric patients 11-16 years of age receiving a single dose of metformin in fixed combination with glyburide, mean dose-normalized glyburide peak plasma concentration and AUC differed less than 6% from historical values in healthy adults.

Following oral administration of 0.5-1.5 g of metformin hydrochloride as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, peak plasma drug concentrations usually are attained within 2-4 hours. Following oral administration of a single dose of metformin hydrochloride as extended-release tablets, peak plasma drug concentrations usually are attained within a median of 7 hours. Following administration of a single dose (0.5-2.5 g) of another extended-release preparation (Glumetza(R)), peak plasma drug concentrations usually are attained within 7-8 hours.

Peak plasma concentrations following administration of metformin extended-release tablets are approximately 20% lower than those following administration of the same dose as immediate-release tablets. The extent of absorption of metformin hydrochloride 2 g once daily as extended-release tablets is similar to that following administration of 1 g of the drug twice daily as immediate-release tablets. Steady-state plasma concentrations with usual dosages of metformin hydrochloride as immediate-release tablets (e.g., 1.5-2.55 g daily in 1 to 3 divided doses) are attained within 24-48 hours.

Satisfactory control of blood or plasma glucose concentration may occur within a few days to 1 week following initiation of metformin therapy in patients with type 2 diabetes mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2 weeks. Following discontinuance of metformin therapy, blood glucose concentration increases within 2 weeks.

Bioequivalence has been demonstrated between the fixed combination of metformin and sitagliptin and each agent given concurrently. Bioequivalence also has been demonstrated between the fixed combination of immediate-release metformin and pioglitazone (ActoPlus Met(R)) and each agent (immediate-release metformin (Glucophage(R)) and pioglitazone (Actos(R))) given concurrently. Results of a bioequivalence study indicate that the fixed-combination tablets of immediate-release metformin hydrochloride and canagliflozin are bioequivalent to the corresponding doses of metformin hydrochloride and canagliflozin given as individual tablets under fed conditions.

Bioequivalence between the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo(R) XR) and each agent (extended-release metformin hydrochloride and dapagliflozin) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo(R) XR) and concomitantly administered dapagliflozin and immediate-release metformin hydrochloride has not been established. Bioequivalence between the fixed-combination tablets of immediate-release metformin hydrochloride and empagliflozin and the corresponding doses of metformin hydrochloride and empagliflozin as individual tablets also has been established. In healthy individuals who received the extended-release metformin hydrochloride preparation (Glumetza(R)) in a single-dose crossover study, a 1-g tablet has been shown to be bioequivalent to two 500-mg tablets based on peak plasma concentrations and AUC.

Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the medication also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues). The highest tissue concentrations of metformin (at least 10 times the plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in kidney, liver, and salivary gland tissue. The medication distributes into salivary glands with a half-life of about 9 hours.

Metformin concentrations in saliva are 10-fold lower than those in plasma and may be responsible for the metallic taste reported in some patients. Any local effect of metformin on glucose absorption in the GI tract may be associated with the relatively high GI concentrations of the medication compared with those in other tissues. Limited data indicate that metformin is distributed into breast milk in humans.

Metformin is negligibly bound to plasma proteins.

Following oral administration of metformin hydrochloride (0.5-1.5 g) as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma concentrations decline in a triphasic manner. The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the medication is cleared within 24 hours in patients with normal renal function. The decline in plasma metformin concentrations is slower after oral than after IV administration, indicating that elimination is absorption rate-limited.

Urinary excretion data and data from whole blood indicate a slower terminal-elimination phase half-life of 8-20 hours (e.g., 17.6 hours) suggesting that the erythrocyte mass may be a compartment of distribution. Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the medication have been identified in humans. Renal elimination of metformin involves glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug.

Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination. Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution. Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, because of reduced renal function with age, in geriatric individuals.

In geriatric individuals, decreased renal and plasma clearance of metformin results in increased plasma concentrations of metformin; volume of distribution remains unaffected. The pharmacokinetics of metformin in patients with normal renal function do not appear to be affected by sex, race, or the presence of diabetes mellitus.

USES: This combination medication is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. It may also be used with other diabetes medications. This product contains 2 medications.

Glyburide belongs to the class of drugs known as sulfonylureas. It lowers blood sugar by causing the release of your body's natural insulin and by decreasing the amount of sugar that your liver makes. Metformin works by decreasing the amount of sugar that your liver makes and that your stomach/intestines absorb.

Both of these medications work by helping to restore your body's proper response to the insulin you naturally produce. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.

Generic name: glyburide/metformin HCl
Pronunciation: (GLYE-bure-ide/met-FOR-min)

The following indications are listed for Glyburide-Metformin:

• Type 2 Diabetes Mellitus

Also known as: Adult Onset Diabetes, Adult Onset Diabetes Mellitus, Adult Onset Dm, Diabetes Mellitus Type 2, Diabetes Mellitus Type Ii, Ketosis-Resistant Diabetes Mellitus, Ketosis-Resistant Dm, Maturity Onset Diabetes, Maturity Onset Diabetes Mellitus, Non-Insulin Dependent Diabetes Mellitus, Non-Insulin-Dependent Diabetes Mellitus, Type Ii Diabetes Mellitus.

No ICD codes are available for this drug.