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This medication contains important usage instructions, warnings, and side effect information that you should review before use.
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.
General Considerations
Dosage of glyburide and metformin hydrochloride tablets 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 tablets 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), reduce GI side effects (largely due to metformin), and 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 tablets 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 tablets 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 Tablets 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 tablets 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 tablet 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 2 weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of glyburide and metformin hydrochloride tablets as initial therapy, there was no experience with total daily doses >10 mg/2000 mg per day. Glyburide and metformin hydrochloride tablet 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.
Glyburide and Metformin Hydrochloride Tablets 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 tablets 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 tablets 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 tablets, 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 tablets should be titrated as described above to achieve adequate control of blood glucose.
Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Tablets Therapy
For patients not adequately controlled on glyburide and metformin hydrochloride tablets, a thiazolidinedione can be added to glyburide and metformin hydrochloride tablets therapy. When a thiazolidinedione is added to glyburide and metformin hydrochloride tablets therapy, the current dose of glyburide and metformin hydrochloride tablets 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 tablets 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 tablets and a thiazolidinedione, consideration should be given to reducing the dose of the glyburide component of glyburide and metformin hydrochloride tablets. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.
Patients Receiving Colesevelam
When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, glyburide and metformin hydrochloride tablets should be administered at least 4 hours prior to colesevelam.
Specific Patient Populations
Glyburide and metformin hydrochloride tablets are not recommended for use during pregnancy. The initial and maintenance dosing of glyburide and metformin hydrochloride tablets 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 tablets 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.)
Glyburide and metformin hydrochloride tablets are contraindicated in patients with:
Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
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
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.
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
Adverse Event Number (%) of Patients
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.
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 1 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 1 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
Variable Placebo
N=161 Glyburide
Tablets
N=160 Metformin
Tablets
N=159 Glyburide and
Metformin
Hydrochloride
1.25 mg/250 mg
Tablets
N=158 Glyburide and
Metformin
Hydrochloride
2.5 mg/500 mg
Tablets
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)
In postmarketing reports cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; glyburide and metformin hydrochloride should be discontinued if this occurs.
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 Tablets, USP
Rx only
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. (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. Why is 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, 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. Glyburide and metformin hydrochloride combines 2 glucose-lowering drugs, glyburide and metformin. These 2 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 to 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 buildup 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 1 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, e.g., 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.
Do not take glyburide and metformin hydrochloride if you are taking bosentan used for pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs.
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.
Trademarks are the property of their respective owners.
Manufactured for:
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810
Manufactured by:
Aurobindo Pharma Limited
Hyderabad–500 090, India
Revised: 07/2015
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 to off-white crystalline compound. The structural formula is represented below.
[Glyburide Chemical Structure]
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 to off-white crystalline compound. 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:
[Metformin Chemical Structure]
Glyburide and metformin hydrochloride tablets, USP are available for oral administration containing 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 film-coated tablet contains the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, hypromellose, propylene glycol, polysorbate 80, talc, titanium dioxide and FD&C Yellow#6 aluminum lake. The 1.25 mg/250 mg and 5 mg/500 mg strengths also contain D&C Yellow#10 aluminum lake; The 2.5 mg/500 mg strength also contains FD&C Red#40 aluminum lake.
[image: img_26182c3b-af32-069c-e054-00144ff88e88]
Photos of the product and/or packaging supplied by the manufacturer.
Mechanism of Action
Glyburide and metformin hydrochloride tablets combine 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 co-administered 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 tablets 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 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism and Elimination
Glyburide
The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400 and 1/40 as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.
Metformin Hydrochloride
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations
Patients With Type 2 Diabetes
Multiple-dose studies with glyburide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.
In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.
Hepatic Insufficiency
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin.
Renal Insufficiency
No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.
In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).
Geriatrics
There is no information on the pharmacokinetics of glyburide in elderly patients.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, when compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Table 1: Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin
Subject Groups: Metformin Dosea
(number of subjects) Cmaxb
(mcg/mL) Tmaxc
(hrs) Renal Clearance
(mL/min)
a All doses given fasting except the first 18 doses of the multiple-dose studies
b Peak plasma concentration
c Time to peak plasma concentration
d SD=single dose
e Combined results (average means) of 5 studies: mean age 32 years (range 23 to 59 years)
f Kinetic study done following dose 19, given fasting
g Elderly subjects, mean age 71 years (range 65 to 81 years)
h CLcr=creatinine clearance normalized to body surface area of 1.73 m2
Healthy, nondiabetic adults:
500 mg SDd (24)
850 mg SD (74)e
850 mg t.i.d. for 19 dosesf (9) 1.03 (±0.33)
1.6 (±0.38)
2.01 (±0.42) 2.75 (±0.81)
2.64 (±0.82)
1.79 (±0.94) 600 (±132)
552 (±139)
642 (±173)
Adults with type 2 diabetes:
850 mg SD (23)
850 mg t.i.d. for 19 dosesf (9) 1.48 (±0.5)
1.9 (±0.62) 3.32 (±1.08)
2.01 (±1.22) 491 (±138)
550 (±160)
Elderlyg, healthy nondiabetic adults:
850 mg SD (12) 2.45 (±0.7) 2.71 (±1.05) 412 (±98)
Renal-impaired adults: 850 mg SD
Mild (CLcrh 61-90 mL/min) (5)
Moderate (CLcr 31-60 mL/min) (4)
Severe (CLcr 10-30 mL/min) (6) 1.86 (±0.52)
4.12 (±1.83)
3.93 (±0.92) 3.2 (±0.45)
3.75 (±0.5)
4.01 (±1.1) 384 (±122)
108 (±57)
130 (±90)
Pediatrics
After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed <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 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.
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
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
a p<0.001
b p<0.05
c p=NS
Mean Final Dose 0 mg 5.3 mg 1317 mg 2.78 mg/557 mg 4.1 mg/824 mg
Hemoglobin A1c N=147 N=142 N=141 N=149 N=152
Baseline Mean (%) 8.14 8.14 8.23 8.22 8.2
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, 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 (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin (500 mg), glyburide and metformin hydrochloride 2.5 mg/500 mg, or glyburide and metformin hydrochloride 5 mg/500 mg. The doses of metformin and glyburide and metformin hydrochloride were titrated to a maximum of 4 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 Sulfonylurea Alone: Summary of Trial Data at 16 Weeks
Glyburide
5 mg
Tablets Metformin
500 mg
Tablets Glyburide and
Metformin
Hydrochloride
2.5 mg/500 mg
Tablets Glyburide and
Metformin
Hydrochloride
5 mg/500 mg
Tablets
a p<0.001
Mean Final Dose 20 mg 1840 mg 8.8 mg/1760 mg 17 mg/1740 mg
Hemoglobin A1c N=158 N=142 N=154 N=159
Baseline Mean (%) 9.63 9.51 9.43 9.44
Final Mean 9.61 9.82 7.92 7.91
Difference from Glyburide -1.69a -1.7a
Difference from Metformin -1.9a -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 221 233.8 169.6 161.1
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 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.
Table 4: Effects of Adding Rosiglitazone or Placebo in Patients Treated with Glyburide and Metformin Hydrochloride in a 24-Week Trial
Placebo +
Glyburide and
Metformin
Hydrochloride Rosiglitazone +
Glyburide and
Metformin
Hydrochloride
a Adjusted for the baseline mean difference
b p<0.001
Mean Final Dose
Glyburide and Metformin Hydrochloride
Rosiglitazone
10 mg/1992 mg
0 mg
9.6 mg/1914 mg
7.4 mg
Hemoglobin A1c N=178 N=177
Baseline Mean (%) 8.09 8.14
Final Mean 8.21 7.23
Difference from 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% 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.
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