Glyburide and metformin

GLUCOVANCE® (Glyburide and Metformin HCl) Tablets

GLUCOVANCE 1.25 mg/250 mg tablet is a pale yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with “BMS” debossed on one side and “6072” debossed on the opposite side.

GLUCOVANCE 2.5 mg/500 mg tablet is a pale orange, capsule-shaped, bevel-edged, biconvex, filmcoated tablet with “BMS” debossed on one side and “6073” debossed on the opposite side.

GLUCOVANCE 5 mg/500 mg tablet is a yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with “BMS” debossed on one side and “6074” debossed on the opposite side.

Storage

Store at temperatures up to 25°C (77°F). [See USP Controlled Room Temperature.]

Dispense in light-resistant containers.

Distributed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA 1158884A7. Rev Oct 2013

Metformin Hydrochloride

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOVANCE (Glyburide and Metformin HCl) Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases /1000 patient-years, with approximately 0.015 fatal cases /1000 patient-years ). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOVANCE treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis . In addition, GLUCOVANCE should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, GLUCOVANCE should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUCOVANCE, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOVANCE should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). GLUCOVANCE should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels , and even blood metformin levels may be useful. Once a patient is stabilized on any dos e level of GLUCOVANCE, gastrointestinal symptoms , which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUCOVANCE do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in s ample handling. (See also PRECAUTIONS.)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking GLUCOVANCE, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions ), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)

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 glucoselowering drugs in preventing or delaying vascular complications in patients with non-insulindependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 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 (1.5g 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 bas is for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy.

Although only 1 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.

In the U.S.

• Glucovance

Available Dosage Forms:

• Tablet

Therapeutic Class: Hypoglycemic, Biguanide/Sulfonylurea Combination

Chemical Class: 2nd Generation Sulfonylurea

Glyburide and metformin combination is used to treat a type of diabetes mellitus called type 2 diabetes. It is used together with a proper diet and exercise to help control blood sugar levels.

Glyburide causes your pancreas to release more insulin into the bloodstream. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better.

glyburide and metformin is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For glyburide and metformin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to glyburide and metformin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of glyburide and metformin combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of glyburide and metformin combination in the elderly. However, elderly patients are more likely to have age-related kidney problems which may require caution and an adjustment in the dose for patients receiving glyburide and metformin combination.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking glyburide and metformin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using glyburide and metformin with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Acetrizoic Acid
• Bosentan
• Diatrizoate
• Ethiodized Oil
• Iobenzamic Acid
• Iobitridol
• Iocarmic Acid
• Iocetamic Acid
• Iodamide
• Iodipamide
• Iodixanol
• Iodohippuric Acid
• Iodopyracet
• Iodoxamic Acid
• Ioglicic Acid
• Ioglycamic Acid
• Iohexol
• Iomeprol
• Iopamidol
• Iopanoic Acid
• Iopentol
• Iophendylate
• Iopromide
• Iopronic Acid
• Ioseric Acid
• Iosimide
• Iotasul
• Iothalamate
• Iotrolan
• Iotroxic Acid
• Ioxaglate
• Ioxitalamic Acid
• Ipodate
• Metrizamide
• Metrizoic Acid
• Tyropanoate Sodium

Using glyburide and metformin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acarbose
• Aspirin
• Balofloxacin
• Besifloxacin
• Bupropion
• Ciprofloxacin
• Dasabuvir
• Disopyramide
• Dofetilide
• Dolutegravir
• Dulaglutide
• Enoxacin
• Entacapone
• Fleroxacin
• Flumequine
• Gatifloxacin
• Gemifloxacin
• Ioversol
• Lanreotide
• Levofloxacin
• Lixisenatide
• Lomefloxacin
• Metreleptin
• Moxifloxacin
• Nadifloxacin
• Norfloxacin
• Octreotide
• Ofloxacin
• Ombitasvir
• Paritaprevir
• Pasireotide
• Pazufloxacin
• Pefloxacin
• Pioglitazone
• Prulifloxacin
• Ritonavir
• Rufloxacin
• Simeprevir
• Sparfloxacin
• Thioctic Acid
• Tosufloxacin
• Vandetanib

Using glyburide and metformin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Aminolevulinic Acid
• Atenolol
• Betaxolol
• Bisoprolol
• Bitter Melon
• Carteolol
• Carvedilol
• Celiprolol
• Clarithromycin
• Colesevelam
• Cyclosporine
• Esmolol
• Fenugreek
• Fluvastatin
• Furazolidone
• Gemfibrozil
• Glucomannan
• Guar Gum
• Iproniazid
• Isocarboxazid
• Labetalol
• Levobunolol
• Linezolid
• Methylene Blue
• Metipranolol
• Metoprolol
• Moclobemide
• Nadolol
• Nebivolol
• Nialamide
• Oxprenolol
• Patiromer
• Penbutolol
• Phenelzine
• Pindolol
• Practolol
• Procarbazine
• Propranolol
• Psyllium
• Ranolazine
• Rasagiline
• Rifampin
• Rifapentine
• Safinamide
• Saxagliptin
• Selegiline
• Sotalol
• Timolol
• Tranylcypromine
• Verapamil
• Voriconazole
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using glyburide and metformin with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use glyburide and metformin, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of glyburide and metformin. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol intoxication or
• Underactive adrenal glands or
• Underactive pituitary gland or
• Undernourished condition or
• Weakened physical condition or
• Any other condition that causes low blood sugar—Patients with these conditions may be more likely to develop low blood sugar while taking glyburide and metformin combination.

• Blood poisoning or
• Dehydration, severe or
• Heart or blood vessel disorders—Lactic acidosis can occur in these conditions and chances of it occurring are even greater with a medicine that contains metformin.

• Diabetic ketoacidosis (high ketones and acid in the blood) or
• Kidney disease, severe or
• Type I diabetes—Should not be used in patients with these conditions.

• Fever or
• Infection or
• Surgery or
• Trauma—These conditions may cause temporary problems with blood sugar control and your doctor may want to treat you temporarily with insulin.

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (an enzyme problem)—May cause hemolytic anemia (a blood disorder) in patients with this condition.

• Heart attack, acute or
• Heart disease (eg, congestive heart failure) or
• Vitamin B12 deficiency—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. Effects may be increased because of slower removal of the medicine from the body.

Glyburide and Metformin Hydrochloride

In double-blind clinical trials involving Glyburide and Metformin hydrochloride as initial therapy or as second-line therapy, a total of 642 patients received the combination product Glyburide and Metformin hydrochloride, 312 received metformin therapy, 324 received glyburide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Glyburide and Metformin hydrochloride (all strengths) as initial therapy and second-line therapy are listed in Table 6.

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

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

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

Hypoglycemia

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

Gastrointestinal Reactions

The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7. Across all Glyburide and Metformin hydrochloride trials, GI symptoms were the most common adverse events with Glyburide and Metformin hydrochloride and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued Glyburide and Metformin hydrochloride therapy due to GI adverse events.

Metformin Hydrochloride

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Glyburide

Gastrointestinal Reactions

Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; the drug should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported.

Dermatologic Reactions

Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use; if skin reactions persist, the drug should be discontinued.

Postmarketing Adverse Reactions

The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.

Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.

Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Glyburide and Metformin Hydrochloride

(glye' bure ide and met for' min hye" droe klor' ide)

 Tablets, USP

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 tablets 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. The Glyburide and Metformin hydrochloride product combines two glucose-lowering drugs, Glyburide and Metformin. These two drugs work together to improve the different metabolic defects found in type 2 diabetes. Glyburide lowers blood sugar primarily by causing more of the body’s own insulin to be released, and metformin lowers blood sugar, in part, by helping your body use your own insulin more effectively. Together, they are efficient in helping you 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 tablets your doctor may prescribe injectable insulin or take other measures to control your diabetes.

Q7. Can Glyburide and Metformin Hydrochloride tablets cause side effects?

Glyburide and Metformin hydrochloride tablets, 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 tablets 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.

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.

Q10. What is lactic acidosis and can it happen to me?

Metformin, one of the medicines in Glyburide and Metformin hydrochloride tablets can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.

Q11. Are there other risk factors for lactic acidosis?

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with Glyburide and Metformin hydrochloride tablets if you:

• have severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye
• have liver problems
• drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking
• get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids
• have surgery
• have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your Glyburide and Metformin hydrochloride tablets for a while if you have any of these things.

Q12. What are the symptoms of lactic acidosis?

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

• you feel cold in your hands or feet
• you feel dizzy or lightheaded
• you have a slow or irregular heartbeat
• you feel very weak or tired
• you have unusual (not normal) muscle pain
• you have trouble breathing
• you feel sleepy or drowsy
• you have stomach pains, nausea or vomiting

Q13. What does my doctor need to know to decrease my risk of lactic acidosis?

Before you take Glyburide and Metformin hydrochloride tablets, tell your doctor if you:

• have severe kidney problems
• have liver problems
• have heart problems, including congestive heart failure
• drink alcohol very often, or drink a lot of alcohol in short term “binge” drinking
• are going to get an injection of dye or contrast agents for an x-ray procedure. Glyburide and Metformin hydrochloride tablets may need to be stopped for a short time. Talk to your doctor about when you should stop Glyburide and Metformin hydrochloride tablets and when you should start Glyburide and Metformin hydrochloride tablets again. See "What is the most important information I should know about Glyburide and Metformin hydrochloride tablets?"
•  have any other medical conditions

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.

Do not take Glyburide and Metformin hydrochloride tablets 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 their side effects. For additional information about Glyburide and Metformin hydrochloride tablets, call Actavis at 1-800-432-8534. There is also a leaflet (prescribing information) written for health professionals that your pharmacist can let you read.

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

Brands listed are the trademarks of their respective owners.

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

40-9179
(PIL 41-1192/0517)

NDC 0228-2751-11

Glyburide and Metformin Hydrochloride Tablets

1.25 mg/250 mg 

100 Tablets

Rx Only

Actavis

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, oral: 1.25 mg/250 mg: Glyburide 1.25 mg and metformin hydrochloride 250 mg; 2.5 mg/500 mg: Glyburide 2.5 mg and metformin hydrochloride 500 mg; 5 mg/500 mg: Glyburide 5 mg and metformin hydrochloride 500 mg

Glucovance: 1.25 mg/250 mg: Glyburide 1.25 mg and metformin hydrochloride 250 mg [DSC]

Glucovance: 2.5 mg/500 mg: Glyburide 2.5 mg and metformin hydrochloride 500 mg

Glucovance: 5 mg/500 mg: Glyburide 5 mg and metformin hydrochloride 500 mg

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antidiabetic Agents (Thiazolidinedione): May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Beta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bosentan: GlyBURIDE may enhance the hepatotoxic effect of Bosentan. GlyBURIDE may increase the metabolism of Bosentan. Bosentan may increase the metabolism of GlyBURIDE. Avoid combination

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chloramphenicol: May decrease the metabolism of Sulfonylureas. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

Clarithromycin: May increase the serum concentration of GlyBURIDE. Monitor therapy

Colesevelam: May decrease the serum concentration of GlyBURIDE. Management: Administer glyburide at least 4 hours prior to colesevelam. Consider therapy modification

Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

CycloSPORINE (Systemic): May diminish the therapeutic effect of GlyBURIDE. GlyBURIDE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Fluconazole: May increase the serum concentration of Sulfonylureas. Management: Seek alternatives when possible. If used together, monitor closely for increased effects of sulfonylureas if fluconazole is initiated/dose increased, or decreased effects if fluconazole is discontinued/dose decreased. Consider therapy modification

GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Metreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Avoid combination

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Probenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RaNITIdine: May increase the serum concentration of Sulfonylureas. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

RifAMPin: May decrease the serum concentration of Sulfonylureas. Management: Seek alternatives to these combinations when possible. Monitor closely for diminished therapeutic effects of sulfonylureas if rifampin is initiated/dose increased, or enhanced effects if rifampin is discontinued/dose decreased. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Voriconazole: May increase the serum concentration of Sulfonylureas. Monitor therapy

Concerns related to adverse effects:

• Cardiovascular mortality: Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS) have not supported an association. Metformin does not appear to share this risk.

• Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished or debilitated patients, and in patients with impaired renal, hepatic, adrenal, and/or pituitary function; use with caution.

• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function and the patient's age.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2017c).

Disease-related concerns:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.

• Heart failure: Use metformin with caution in patients with heart failure requiring pharmacologic management, particularly in patients with unstable or acutely decompensated heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

• Hepatic impairment: The metabolism and excretion of glyburide may be slowed in patients with hepatic impairment; if hypoglycemia should occur in such patients, it may be prolonged. Use metformin with caution in patients with impaired liver function due to potential for lactic acidosis.

• Renal impairment: The metabolism and excretion of glyburide may be slowed in patients with renal impairment and its active metabolites may accumulate in advanced renal insufficiency (Snyder 2004). If hypoglycemia should occur, it may be prolonged. Metformin is substantially excreted by the kidney and use is contraindicated in patients with eGFR <30 mL/minute/1.73 m2. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; risk of metformin-associated lactic acidosis increases with age.

Other warnings/precautions:

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: Temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015).

• Surgical procedures: Metformin should be withheld 24 hours before surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2017d). Resume only after normal intake returns and normal renal function is verified.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, abdominal pain, nausea, vomiting, diarrhea, common cold symptoms, or dizziness. Have patient report immediately to prescriber signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), severe loss of strength and energy, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer:Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Applies to glyburide / metformin: oral tablet

General

The most commonly reported adverse reactions include hypoglycemia, upper respiratory infection, gastrointestinal events, and dizziness.[Ref]

Metabolic

In clinical trials, all hypoglycemic episodes were managed by patients, no episodes required medical intervention or pharmacologic therapy. The incidence of hypoglycemia was highest in patients with a baseline HbA1c less than 7%. For patients with a baseline HbA1c between 8% and 11% receiving glyburide 2.5 mg-metformin 500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on a sulfonylurea alone, 6.8% of patients experienced hypoglycemic episodes. The addition of rosiglitazone resulted in 22% of patients reporting a fingerstick glucose measurement of 50 mg/DL or lower (compared to 3.3% of placebo patients). Additionally in rosiglitazone-treated patients, a mean weight gain of 3 kg was observed.

Metabolic side effects, including lactic acidosis, which is a potentially fatal metabolic complication of biguanide therapy, has been reported in patients receiving metformin. The incidence of lactic acidosis has been about 0.03 cases per 1,000 patient years with approximately 0.015 fatal cases per 1,000 patient-years. The risk of lactic acidosis is particularly high in patients with underlying renal insufficiency. Cases of lactic acidosis occurring in patients with normal renal function have been rarely reported. Concomitant cardiovascular or liver disease, sepsis, and hypoxia may also increase the risk of lactic acidosis.

Glyburide-Metformin:
Very common (10% or more): Hypoglycemia (up to 37.7%)
Very rare (less than 0.01%): Disulfiram-like reactions
Frequency not reported: Weight gain, hypoglycemic coma, elevated blood glucose level, dehydration, metabolic acidosis

Glyburide:
Very common (10% or more): Hypoglycemia (21.3%)
Very rare (less than 0.01%): Disulfiram-like reactions, hyponatremia
Frequency not reported: Moderate elevations in serum urea and creatinine concentrations

Metformin:
Common (1% to 10%): Hypoglycemia
Rare (less than 0.1%): Lactic acidosis

Gastrointestinal

The incidence of gastrointestinal (GI) side effects including diarrhea, nausea/vomiting, and abdominal pain in the initial therapy trials were 31.6% (50/158) and 38.3% (n=62/162) in the glyburide 1.25 mg-metformin 250 mg and the glyburide 2.5 mg-metformin 500 mg groups, respectively. Across all trials, GI symptoms were the most common adverse event and were more frequent at higher dose levels; less than 2% of patients discontinued therapy due to GI adverse events.[Ref]

Glyburide-Metformin:
Very common (10% or more): Diarrhea (17%)
Common (1% to 10%): Nausea/vomiting, abdominal pain
Frequency not reported: Pancreatitis, acute gallstone pancreatitis, gastrointestinal hemorrhage[Ref]

Hematologic

Glyburide-Metformin:
Frequency not reported: Disseminated intravascular coagulation, hemorrhage

Glyburide:
Rare (less than 0.1%): Agranulocytosis, eosinophilia, hemolytic anemia, aplastic anemia, bone marrow aplasia, pancytopenia, coagulation disorders
Frequency not reported: Leukopenia, thrombocytopenia, thrombocytopenia purpura
Postmarketing reports: Hemolytic anemia in patients not known to have G6PD deficiency

Metformin:
Common (1% to 10%): Subnormal vitamin B12 levels
Frequency not reported: Anemia[Ref]

Respiratory

Glyburide-Metformin:
Very common (10% or more): Upper respiratory infection (17.3%)
Frequency not reported: Pulmonary hypertension[Ref]

Nervous system

Glyburide-Metformin:
Common (1% to 10%): Headache, dizziness
Frequency not reported: Dystonia, involuntary muscle contractions, grand mal seizure, unconsciousness, unresponsiveness

Glyburide:
Frequency not reported: Paresthesia, tremor, convulsions, encephalopathy, cerebrovascular disorders, headache,

Metformin:
Common (1% to 10%): Taste disturbances[Ref]

Dermatologic

Glyburide-Metformin:
Frequency not reported: Dermatitis

Glyburide:
Common (1% to 10%): Pruritus, erythema, urticaria erythematous, maculopapular rash and bullous skin eruptions or psoriasiform drug eruption
Frequency not reported: Alopecia/hypotrichosis, angioedema, facial edema, increased sweating

Sulfonylureas:
Very rare (less than 0.01%): cutaneous or visceral allergic angitis, exfoliative dermatitis, urticaria evolving to shock
Frequency not reported: Porphyria cutanea tarda, pellagra-like changes, photosensitization

Metformin:
Rare (less than 0.1%): Skin reactions such as erythema, pruritus and urticaria[Ref]

Hypersensitivity

Sulfonylureas:
Frequency not reported: Cross-reactivity to sulfonamide(s) and their derivatives[Ref]

Hepatic

Glyburide-Metformin
Frequency not reported: Cholethiasis

Metformin:
Very rare (less than 0.01%): Liver function test abnormalities, hepatitis
Postmarketing reports: Cholestatic jaundice

Sulfonylureas:
Frequency not reported: Hepatic porphyria, increased liver enzymes (AST, ALT), abnormal liver function, cholestasis, cholestatic hepatitis, granulomatous hepatitis, and bilirubinemia[Ref]

Renal

Glyburide-Metformin:
Frequency not reported: Acute renal failure

Glyburide:
Frequency not reported: Abnormal renal function, acute renal failure[Ref]

Ocular

Glyburide:
Frequency not reported: Transient visual disturbances at the start of treatment (due to decrease in glycemic levels), blindness, diplopia, visual disturbances, ocular disturbances (accommodation changes, crystalline lens changes)[Ref]

Cardiovascular

Glyburide-Metformin:
Common (1% to 10%): Edema
Frequency not reported: Myocardial infarction, tachycardia, chest pain[Ref]

In add-on rosiglitazone clinical trials, edema was reported in 7.7% (14/181) patients compared to 2.2% in placebo patients.[Ref]

Endocrine

Glyburide:
Frequency not reported: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)[Ref]

Musculoskeletal

Glyburide:
Frequency not reported: Arthralgia, arthritis[Ref]

Psychiatric

Glyburide-Metformin:
Frequency not reported: Disorientation

Glyburide:
Frequency not reported: Confusion, acute psychosis[Ref]

Other

Glyburide:
Frequency not reported: Deafness[Ref]

Some side effects of glyburide / metformin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

No data available.