Mechanism of Action

Glyburide and metformin hydrochloride tablets contain two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacokinetics

Special Populations

Clinical Studies

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

General

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted with the combined products in glyburide and metformin hydrochloride. The following data are based on findings in studies performed with the individual products.

Glyburide

Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily [MRHD] dose of 20 mg for the glyburide component of glyburide and metformin hydrochloride based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a two-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors.

There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.

Metformin Hydrochloride

Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the MRHD dose of 2000 mg of the metformin component of glyburide and metformin hydrochloride based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.

There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately three times the MRHD dose of the metformin component of glyburide and metformin hydrochloride based on body surface area comparisons.

Teratogenic Effects: Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, glyburide and metformin hydrochloride should not be used during pregnancy unless clearly needed. (See below.)

There are no adequate and well-controlled studies in pregnant women with glyburide and metformin hydrochloride or its individual components. No animal studies have been conducted with the combined products in glyburide and metformin hydrochloride. The following data are based on findings in studies performed with the individual products.

Glyburide

Reproduction studies were performed in rats and rabbits at doses up to 500 times the MRHD dose of 20 mg of the glyburide component of glyburide and metformin hydrochloride based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to glyburide.

Metformin Hydrochloride

Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the 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.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that glyburide and metformin hydrochloride be used during pregnancy. However, if it is used, glyburide and metformin hydrochloride should be discontinued at least two weeks before the expected delivery date. (See Pregnancy: Teratogenic Effects: Pregnancy Category B.)

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue glyburide and metformin hydrochloride, taking into account the importance of the drug to the mother. If glyburide and metformin hydrochloride is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and efficacy of glyburide and metformin hydrochloride 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.

Geriatric Use

Of the 642 patients who received glyburide and metformin hydrochloride in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received glyburide and metformin hydrochloride in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, glyburide and metformin hydrochloride should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, glyburide and metformin hydrochloride should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of glyburide and metformin hydrochloride (see also WARNINGS and DOSAGE AND ADMINISTRATION).

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.

In a controlled clinical trial of rosiglitazone versus placebo in patients treated with glyburide and metformin hydrochloride (n=365), 181 patients received glyburide and metformin hydrochloride with rosiglitazone and 184 received glyburide and metformin hydrochloride with placebo.

Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184) of patients treated with placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated patients.

Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.

Hypoglycemia

In controlled clinical trials of glyburide and metformin hydrochloride there were no hypoglycemic episodes requiring medical intervention and/or pharmacologic therapy; all events were managed by the patients. The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of glyburide and metformin hydrochloride are summarized in Table 7. The frequency of hypoglycemic symptoms in patients treated with glyburide and metformin hydrochloride 1.25 mg/250 mg was highest in patients with a baseline HbA1c <7%, lower in those with a baseline HbA1c of between 7% and 8%, and was comparable to placebo and metformin in those with a baseline HbA1c >8%. For patients with a baseline HbA1c between 8% and 11% treated with glyburide and metformin hydrochloride 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with glyburide and metformin hydrochloride experienced hypoglycemic symptoms. When rosiglitazone was added to glyburide and metformin hydrochloride therapy, 22% of patients reported one or more fingerstick glucose measurements ≤50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were managed by the patients and only one patient discontinued for hypoglycemia.(See PRECAUTIONS: General: Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy.)

Gastrointestinal Reactions

The incidences 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.

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.

General Considerations

Dosage of glyburide and metformin hydrochloride must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glyburide/2000 mg metformin. Glyburide and metformin hydrochloride should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glyburide), 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 and to identify the minimum effective dose for the patient. Thereafter, HbA1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone.

No studies have been performed specifically examining the safety and efficacy of switching to glyburide and metformin hydrochloride therapy in patients taking concomitant glyburide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.

Glyburide and Metformin Hydrochloride in Patients with Inadequate Glycemic Control on Diet and Exercise

Recommended starting dose:  1.25 mg/250 mg once or twice daily with meals.

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of glyburide and metformin hydrochloride is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with baseline HbA1c >9% or an FPG >200 mg/dL, a starting dose of glyburide and metformin hydrochloride 1.25 mg/250 mg twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg/250 mg per day every two weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of glyburide and metformin hydrochloride as initial therapy, there was no experience with total daily doses >10 mg/2000 mg per day. Glyburide and metformin hydrochloride 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.

Glyburide and Metformin Hydrochloride Use in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin

Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.

For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin alone, the recommended starting dose of glyburide and metformin hydrochloride is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of glyburide and metformin hydrochloride should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

For patients previously treated with combination therapy of glyburide (or another sulfonylurea) plus metformin, if switched to glyburide and metformin hydrochloride, the starting dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of glyburide and metformin hydrochloride should be titrated as described above to achieve adequate control of blood glucose.

Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy

For patients not adequately controlled on glyburide and metformin hydrochloride, a thiazolidinedione can be added to glyburide and metformin hydrochloride therapy. When a thiazolidinedione is added to glyburide and metformin hydrochloride therapy, the current dose of glyburide and metformin hydrochloride can be continued and the thiazolidinedione initiated at its recommended starting dose. For patients needing additional glycemic control, the dose of the thiazolidinedione can be increased based on its recommended titration schedule. The increased glycemic control attainable with glyburide and metformin hydrochloride plus a thiazolidinedione may increase the potential for hypoglycemia at any time of day. In patients who develop hypoglycemia when receiving glyburide and metformin hydrochloride and a thiazolidinedione, consideration should be given to reducing the dose of the glyburide component of glyburide and metformin hydrochloride. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.

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 is not recommended for use during pregnancy. The initial and maintenance dosing of glyburide and metformin hydrochloride should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of glyburide and metformin hydrochloride to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly. (See WARNINGS.)

Q1. Why do I need to take glyburide and metformin hydrochloride tablets?

Your doctor has prescribed glyburide and metformin hydrochloride tablets 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 tablets, you should still exercise and follow the diet recommended for your diabetes.

Q5. Does glyburide and metformin hydrochloride tablets work differently from other glucose-control medications?

Yes, it does. Glyburide and metformin hydrochloride tablets combine two glucose-lowering drugs, glyburide and metformin. These two drugs work together to improve the different metabolic defects found in type 2 diabetes. Glyburide lowers blood sugar primarily by causing more of the body’s own insulin to be released, and metformin lowers blood sugar, in part, by helping your body use your own insulin more effectively. Together, they are efficient in helping you achieve better glucose control.

Q6.  What happens if my blood sugar is still too high?

When blood sugar cannot be lowered enough by glyburide and metformin hydrochloride your doctor may prescribe injectable insulin or take other measures to control your diabetes.

Q7. Can glyburide and metformin hydrochloride cause side effects?

Glyburide and metformin hydrochloride, like all blood sugar-lowering medications, can cause side effects in some patients. Most of these side effects are minor. However, there are also serious, but rare, side effects related to glyburide and metformin hydrochloride tablets (see Q9 to Q13).

Q8. What are the most common side effects of glyburide and metformin hydrochloride tablets?

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 tablets 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.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Q9.  Are there any serious side effects that glyburide and metformin hydrochloride tablets can cause?

People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take glyburide and metformin hydrochloride tablets 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 tablets.

Glyburide and metformin hydrochloride tablets rarely causes serious side effects. The most serious side effect that glyburide and metformin hydrochloride tablets can cause is called lactic acidosis.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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 one in 33,000 patients taking metformin over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.

It’s also important for your liver to be working normally when you take glyburide and metformin hydrochloride tablets. 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 tablets 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 tablets 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 tablets 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 tablets with other medications?

Remind your doctor that you are taking glyburide and metformin hydrochloride tablets when any new drug is prescribed or a change is made in how you take a drug already prescribed. Glyburide and metformin hydrochloride tablets may interfere with the way some drugs work and some drugs may interfere with the action of glyburide and metformin hydrochloride tablets.

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 tablets?

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 tablets 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 tablets if you are nursing a child.

Q16. How do I take glyburide and metformin hydrochloride tablets?

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 tablets 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 tablets?

This leaflet is a summary of the most important information about glyburide and metformin hydrochloride tablets. 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 tablets and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.

Brands listed are the trademarks of their respective owners.

LB# 262-03

Rev. August, 2014


Manufactured by:
CorePharma, LLC
Middlesex, NJ 08846