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Glyburide and Metformin Hydrochloride
Tablets, USPRx only · Zydus Lifesciences Limited
Glyburide and Metformin Hydrochloride Tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
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.
- Concomitant administration of bosentan.
Glyburide and metformin hydrochloride tablets 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.)
Glyburide and Metformin Hydrochloride
Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control.
These drugs include 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 When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for hypoglycemia.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.
An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of glyburide and metformin hydrochloride and bosentan is contraindicated.
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.
Colesevelam: Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and Cmax of 32% and 47%, respectively. The reductions in glyburide AUC and Cmax were 20% and 15%, respectively, when administered 1 hour before, and not significantly changed (−7% and 4%, respectively) when administered 4 hours before colesevelam.
Metformin Hydrochloride
Furosemide
A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood 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 coadministered chronically.
Nifedipine
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration 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.
Other
In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.
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 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 .
|
|
Number
(%)
of
Patients
|
|
|
|
|
Adverse
Event
|
Placebo
N = 161 |
Glyburide
N
=
324
|
Metformin
N
=
312
|
Glyburide
and
Metformin
Hydrochloride
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) |
| 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) |
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.
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 2 and 6 times the MRHD 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.
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.
The safety and efficacy of glyburide and metformin hydrochloride were 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
2 . 5 mg tablets |
Metformin
500
mg
tablets |
Glyburide
and
Metformin
Hydrochloride
1 . 25 mg / 250 mg tablets |
|
Mean
Final
Dose
|
6.5 mg |
1500 mg |
3.1 mg/623 mg |
|
Hemoglobin
A1
c
|
N=49 |
N=54 |
N=57 |
| Baseline Mean (%) |
7.7 |
7.99 |
7.85 |
| Mean Change from Baseline |
−0.96 |
−0.48 |
−0.80 |
| Difference from Metformin |
|
|
−0.32 |
| Difference from Glyburide |
|
|
0.16 |
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 ).
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.
Glyburide and Metformin Hydrochloride
Patients should be informed of the potential risks and benefits of glyburide and metformin hydrochloride and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program; and 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 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.)
Glyburide and Metformin Hydrochloride Tablets, USP contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide, USP and metformin hydrochloride, USP.
Glyburide, USP 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, USP is a white or almost white, crystalline powder with a molecular formula of C23H28ClN3O5S and a molecular weight of 494. The glyburide used in glyburide and metformin hydrochloride tablets, USP has a particle size at least 20% are less than 2 micron, at least 80% are less than 10 micron and 100% are less than 40 micron. The structural formula is represented below.
[image: MM1]Metformin hydrochloride, USP 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 crystals with a molecular formula of C4H12ClN5 (monohydrochloride) and a molecular weight of 165.62. Metformin hydrochloride, USP is freely soluble in water, slightly soluble in ethanol (95%), practically insoluble in acetone and in methylene chloride. The structural formula is as shown:
[image: MM2]Each glyburide and metformin hydrochloride tablet, USP intended for oral administration contains 1.25 mg glyburide USP with 250 mg metformin hydrochloride USP, 2.5 mg glyburide USP with 500 mg metformin hydrochloride USP and 5 mg glyburide USP with 500 mg metformin hydrochloride USP. In addition, each tablet contains the following inactive ingredients: calcium carbonate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and povidone.
Additionally, 1.25 mg/250 mg tablets contain opadry II white 33F28398 which contains hypromellose, lactose monohydrate, polyethylene glycol, talc and titanium dioxide.
Additionally, 2.5 mg/500 mg tablets contain opadry II orange 31F530003 which contains FD&C blue #2 aluminum lake, FD&C yellow #5 aluminum lake, FD&C yellow #6 aluminum lake, hypromellose, lactose monohydrate, polyethylene glycol and titanium dioxide.
Additionally, 5 mg/500 mg tablets contain opadry II green 31F510000 which contains iron oxide black, iron oxide red, iron oxide yellow, hypromellose, lactose monohydrate, polyethylene glycol and titanium dioxide.
NDC 65841-824-01 in bottles of 100 tablets
Glyburide and Metformin Hydrochloride Tablets USP, 1.25 mg/250 mg
100 Tablets
Rx only
Zydus
[image: MM3]NDC 65841-825-01 in bottles of 100 tablets
Glyburide and Metformin Hydrochloride Tablets USP, 2.5 mg/500 mg
100 Tablets
Rx only
Zydus
[image: MM4]NDC 65841-826-01 in bottles of 100 tablets
Glyburide and Metformin Hydrochloride Tablets USP, 5 mg/500 mg
100 Tablets
Rx only
Zydus
[image: MM5]Glyburide and Metformin Hydrochloride Tablets USP, 1.25 mg/250 mg are white to off white colored, capsule shaped, biconvex coated tablets, debossed with "653" on one side and plain on the other side and are supplied as follows:
NDC 65841-824-06 in bottles of 30 tablets
NDC 65841-824-16 in bottles of 90 tablets
NDC 65841-824-01 in bottles of 100 tablets
NDC 65841-824-05 in bottles of 500 tablets
NDC 65841-824-10 in bottles of 1000 tablets
NDC 65841-824-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Glyburide and Metformin Hydrochloride Tablets USP, 2.5 mg/500 mg are tan to scarlet yellow colored, capsule shaped, biconvex coated tablets debossed with "654" on one side and plain on the other side and are supplied as follows:
NDC 65841-825-06 in bottles of 30 tablets
NDC 65841-825-16 in bottles of 90 tablets
NDC 65841-825-01 in bottles of 100 tablets
NDC 65841-825-05 in bottles of 500 tablets
NDC 65841-825-10 in bottles of 1000 tablets
NDC 65841-825-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Glyburide and Metformin Hydrochloride Tablets USP, 5 mg/500 mg are pale yellow colored, capsule shaped, biconvex coated tablets, debossed with "655" on one side and plain on the other side and are supplied as follows:
NDC 65841-826-06 in bottles of 30 tablets
NDC 65841-826-16 in bottles of 90 tablets
NDC 65841-826-01 in bottles of 100 tablets
NDC 65841-826-05 in bottles of 500 tablets
NDC 65841-826-10 in bottles of 1000 tablets
NDC 65841-826-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
STORAGE
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight container (USP).
GLUCOPHAGE® is a registered trademark of Merck SantÉ S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.
Micronase® is a registered trademark of Pharmacia & Upjohn Company.
Manufactured by:
Cadila Healthcare Ltd.
Baddi, India
Rev.: 03/16
Revision Date: 11/03/16
What it looks like
Photos of the product and/or packaging supplied by the manufacturer.
Package codes (NDC)
- 65841-824-01
- 65841-824-05
- 65841-824-06
- 65841-824-10
- 65841-824-16
- 65841-824-30
- 65841-824-77
- 65841-825-01
- 65841-825-05
- 65841-825-06
- 65841-825-10
- 65841-825-16
- 65841-825-30
- 65841-825-77
- 65841-826-01
- 65841-826-05
- 65841-826-06
- 65841-826-10
- 65841-826-16
- 65841-826-30
- 65841-826-77
Full prescribing information (for healthcare professionals)
CLINICAL PHARMACOLOGY
Mechanism of Action
Glyburide and metformin hydrochloride tablet combines glyburide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Pharmacokinetics
Absorption and Bioavailability
Glyburide and Metformin Hydrochloride
In bioavailability studies of glyburide and metformin hydrochloride 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of the Micronase® brand of glyburide coadministered with metformin. The glyburide component of glyburide and metformin hydrochloride, therefore, is not bioequivalent to Micronase®. The metformin component of glyburide and metformin hydrochloride is bioequivalent to metformin coadministered with glyburide.
Following administration of a single glyburide and metformin hydrochloride 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Cmax and a relatively small effect of food on the AUC of the glyburide component. The Tmax for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.
Glyburide
Single-dose studies with Micronase® tablets in normal subjects demonstrate significant absorption of glyburide within 1 hour, peak drug levels at about 4 hours, and low but detectable levels at 24 hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between glyburide and metformin hydrochloride and single-ingredient glyburide products.
Metformin Hydrochloride
The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
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 4 weeks, the dose was progressively increased (up to the 8-week visit) to a maximum of 4 tablets daily as needed to reach a target FPG of 126 mg/dL. Trial data at 20 weeks are summarized in Table 2 .
|
|
Placebo
|
Glyburide
2
.
5
mg
tablets
|
Metformin
500
mg
tablets
|
Glyburide
and
Metformin
Hydrochloride
1
.
25
mg
/
250
mg
tablets
|
Glyburide
and
Metformin
Hydrochloride
2
.
5
mg
/
500
mg
tablets
|
|
Mean
Final
Dose
|
0 mg |
5.3 mg |
1317 mg |
2.78 mg/557 mg |
4.1 mg/824 mg |
|
Hemoglobin
A1
c
|
N=147 |
N=142 |
N=141 |
N=149 |
N=152 |
| Baseline Mean (%) |
8.14 |
8.14 |
8.23 |
8.22 |
8.2 |
| Mean Change from Baseline |
−0.21 |
−1.24 |
−1.03 |
−1.48 |
−1.53 |
| Difference from Placebo |
|
−1.02 |
−0.82 |
−1.26
|
−1.31
|
| Difference from Glyburide |
|
|
|
−0.24
|
−0.29
|
| Difference from Metformin |
|
|
|
−0.44
|
−0.49
|
|
Fasting
Plasma
Glucose
|
N=159 |
N=158 |
N=156 |
N=153 |
N=154 |
| Baseline Mean FPG (mg/dL) |
177.2 |
178.9 |
175.1 |
178 |
176.6 |
| Mean Change from Baseline |
4.6 |
−35.7 |
−21.2 |
−41.5 |
−40.1 |
| Difference from Placebo |
|
−40.3 |
−25.8 |
−46.1
|
−44.7
|
| Difference from Glyburide |
|
|
|
−5.8
|
−4.5
|
| Difference from Metformin |
|
|
|
−20.3
|
−18.9
|
|
Body
Weight
Mean
Change from Baseline |
−0.7 kg |
+1.7 kg |
−0.6 kg |
+1.4 kg |
+1.9 kg |
|
Final
HbA1
c
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, 3 out of 173 patients (1.7%) discontinued because of inadequate therapeutic response.
Across the group of 144 patients who completed 26 weeks of treatment, mean HbA1c was reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/dL and reduced to 164 and 161 mg/dL after 2 and 26 weeks, respectively. The mean final titrated dose of glyburide and metformin hydrochloride was 7.85 mg/1569 mg (equivalent to approximately 3 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 4 tablets daily as needed to achieve FPG <140 mg/dL. Trial data at 16 weeks are summarized in Table 3 .
|
|
Glyburide
5
mg
tablets
|
Metformin
500
mg
tablets
|
Glyburide
and
Metformin
Hydrochloride
2
.
5
mg
/
500
mg
tablets
|
Glyburide
and
Metformin
Hydrochloride
5 mg / 500 mg tablets |
|
Mean
Final
Dose
|
20 mg |
1840 mg |
8.8 mg/1760 mg |
17 mg/1740 mg |
|
Hemoglobin
A1
c
|
N=158 |
N=142 |
N=154 |
N=159 |
| Baseline Mean (%) |
9.63 |
9.51 |
9.43 |
9.44 |
| Final Mean |
9.61 |
9.82 |
7.92 |
7.91 |
| Difference from Glyburide |
|
|
−1.69 |
−1.70 |
| Difference from Metformin |
|
|
−1.90 |
−1.91 |
|
Fasting
Plasma
Glucose
|
N=163 |
N=152 |
N=160 |
N=160 |
| Baseline Mean (mg/dL) |
218.4 |
213.4 |
212.2 |
210.2 |
| Final Mean |
221 |
233.8 |
169.6 |
161.1 |
| Difference from Glyburide |
|
|
−51.3 |
−59.9 |
| Difference from Metformin |
|
|
−64.2 |
−72.7 |
|
Body
Weight
Mean
Change from Baseline |
+0.43 kg |
−2.76 kg |
+0.75 kg |
+0.47 kg |
|
Final
HbA1
c
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 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% 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 8 weeks, the rosiglitazone dose was increased to a maximum of 8 mg daily as needed to reach a target mean daily glucose of 126 mg/dL or HbA1c <7%. Trial data at 24 weeks or the last prior visit are summarized in Table 4 .
|
|
Placebo
+
Glyburide and Metformin Hydrochloride |
Rosiglitazone
+
Glyburide and Metformin Hydrochloride |
|
Mean
Final
Dose
|
|
|
|
Glyburide
and
Metformin
Hydrochloride
|
10 mg/1992 mg |
9.6 mg/1914 mg |
|
Rosiglitazone
|
0 mg |
7.4 mg |
|
Hemoglobin
A1
c
|
N=178 |
N=177 |
| Baseline Mean (%) |
8.09 |
8.14 |
| Final Mean |
8.21 |
7.23 |
| Difference from Placebo |
|
−1.02 |
|
Fasting
Plasma
Glucose
|
N=181 |
N=176 |
| Baseline Mean (mg/dL) |
173.1 |
178.4 |
| Final Mean |
181.4 |
136.3 |
| Difference from Placebo |
|
−48.5 |
|
Body
Weight
Mean
Change
from
Baseline
|
+0.03 kg |
+3.03 kg |
|
Final
HbA1
c
Distribution
(%)
|
N=178 |
N=177 |
| <7% |
13.5% |
42.4% |
| ≥7% and <8% |
32% |
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.