GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS

Glipizide and metformin hydrochloride tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, glipizide and metformin hydrochloride.

Glipizide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea. Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. The structural formula is represented below.

C₂₁H₂₇N₅O₄S M.W. 445.55

Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

C₄H₁₂ClN₅ M.W. 165.63

Glipizide and metformin hydrochloride is available for oral administration in tablets containing 2.5 mg glipizide with 250 mg metformin hydrochloride, 2.5 mg glipizide with 500 mg metformin hydrochloride, and 5 mg glipizide with 500 mg metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, povidone, starch, talc, and titanium dioxide. Additionally, 2.5 mg/250 mg and 5 mg/500 mg tablets contain iron oxide black, iron oxide red, and iron oxide yellow. The tablets are film coated, which provides color differentiation.

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

Glipizide 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. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the post prandial insulin response continues to be enhanced after at least 6 months of treatment.

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.

Glipizide and metformin hydrochloride tablets are indicated as initial therapy, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone.

Glipizide and metformin hydrochloride tablets are indicated as second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes.

Glipizide and metformin hydrochloride tablets are contraindicated in patients with:

• Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
• Congestive heart failure requiring pharmacologic treatment.
• Known hypersensitivity to glipizide or metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Glipizide and metformin hydrochloride tablets should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)

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 grams 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 glipizide 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.

Periodic fasting blood glucose and glycosylated hemoglobin (HbA_1c) measurements should be performed to monitor therapeutic response.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B₁₂ deficiency should be excluded.

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

Although it is not known whether glipizide 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 glipizide and metformin hydrochloride tablets, taking into account the importance of the drug to the mother. If glipizide and metformin hydrochloride tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Safety and effectiveness of glipizide and metformin hydrochloride tablets in pediatric patients have not been established.

Of the 345 patients who received glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received glipizide and metformin hydrochloride tablets in the second-line therapy trial, 17 (19.5%) were aged 65 and older while one (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, 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, glipizide and metformin hydrochloride tablets 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, glipizide and metformin hydrochloride tablets 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 glipizide and metformin hydrochloride tablets (see also WARNINGS and DOSAGE AND ADMINISTRATION).

In a double-blind 24 week clinical trial involving glipizide and metformin hydrochloride tablets as initial therapy, a total of 172 patients received glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, 173 received glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most common clinical adverse events in these treatment groups are uled in Table 4.

In a double-blind 18 week clinical trial involving glipizide and metformin hydrochloride tablets as second-line therapy, a total of 87 patients received glipizide and metformin hydrochloride tablets, 84 received glipizide, and 75 received metformin. The most common clinical adverse events in this clinical trial are uled in Table 5.

Overdosage of sulfonylureas, including glipizide, 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. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

Among cases of overdosage of metformin hydrochloride, including ingestion of amounts greater than 100 grams, hypoglycemia was reported in approximately 10%, but no causal association with metformin hydrochloride has been established, although lactic acidosis has occurred in such circumstances (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.

Dosage of glipizide and metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glipizide/2000 mg metformin. Glipizide and metformin hydrochloride tablets should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glipizide), to reduce GI side effects (largely due to metformin), and to 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 glipizide and metformin hydrochloride tablets and to identify the minimum effective dose for the patient. Thereafter, HbA_1c 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 HbA_1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA_1c (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 glipizide and metformin hydrochloride tablet therapy in patients taking concomitant glipizide (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.

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of glipizide and metformin hydrochloride tablets is 2.5 mg/250 mg once a day with a meal. For patients whose FPG is 280 to 320 mg/dL a starting dose of glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg twice daily should be considered. The efficacy of glipizide and metformin hydrochloride tablets in patients whose FPG exceeds 320 mg/dL has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of one tablet per day every two weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg glipizide and metformin hydrochloride tablets per day given in divided doses. In clinical trials of glipizide and metformin hydrochloride tablets as initial therapy, there was no experience with total daily doses greater than 10 mg/2000 mg per day.

For patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone, the recommended starting dose of glipizide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of glipizide and metformin hydrochloride tablets should not exceed the daily doses of glipizide 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.

Patients previously treated with combination therapy of glipizide (or another sulfonylurea) plus metformin may be switched to glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg or 5 mg/500 mg; the starting dose should not exceed the daily dose of glipizide (or equivalent dose of another sulfonylurea) and metformin already being taken. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of glipizide and metformin hydrochloride tablets should be titrated as described above to achieve adequate control of blood glucose.

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

Glipizide and metformin hydrochloride tablets are available as follows:

2.5 mg/250 mg are pink, film-coated, modified capsule-shaped tablets, debossed with the “93” on one side and “7455” on the other in bottles of 100.

2.5 mg/500 mg are white, film-coated, modified capsule-shaped tablets, debossed with the “93” on one side and “7456” on the other in bottles of 100.

5 mg/500 mg are pink, film-coated, modified capsule-shaped tablets, debossed with the “93” on one side and “7457” on the other in bottles of 100.

STORAGE

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

WARNING: A small number of people who have taken metformin hydrochloride have developed a serious condition called lactic acidosis. Properly functioning kidneys are needed to help prevent lactic acidosis. Most people with kidney problems should not take glipizide and metformin hydrochloride tablets. (See Question Nos. 9 to 13.)

Q1. WHY DO I NEED TO TAKE GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS?

Your doctor has prescribed glipizide 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, by a number of oral medications, and by insulin injections. Before taking glipizide and metformin hydrochloride tablets you should first try to control your diabetes by exercise and weight loss. Even if you are taking glipizide and metformin hydrochloride tablets, you should still exercise and follow the diet recommended for your diabetes.

Q5. DOES GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS WORK DIFFERENTLY FROM OTHER GLUCOSE-CONTROL MEDICATIONS?

Yes it does. Glipizide and metformin hydrochloride tablets combine two glucose lowering drugs, glipizide and metformin. These two drugs work together to improve the different metabolic defects found in type 2 diabetes. Glipizide 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 glipizide and metformin hydrochloride tablets your doctor may prescribe injectable insulin or take other measures to control your diabetes.

Q7. CAN GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS CAUSE SIDE EFFECTS?

Glipizide 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 glipizide and metformin hydrochloride tablets (see Question Nos. 9 to 13).

Q8. WHAT ARE THE MOST COMMON SIDE EFFECTS OF GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS?

The most common side effects of glipizide 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 glipizide and metformin hydrochloride tablets with meals can help reduce these side effects.

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 GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS CAN CAUSE?

Glipizide and metformin hydrochloride tablets rarely cause serious side effects. The most serious side effect that glipizide and metformin hydrochloride tablets can cause is called lactic acidosis.

Q10. WHAT IS LACTIC ACIDOSIS AND CAN IT HAPPEN TO ME?

Lactic acidosis is caused by a buildup of lactic acid in the blood. Lactic acidosis associated with metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about 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 glipizide 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 glipizide and metformin hydrochloride tablets cause harm to the kidneys or liver.

Q11. ARE THERE OTHER RISK FACTORS FOR LACTIC ACIDOSIS?

Your risk of developing lactic acidosis from taking glipizide 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 physician.

You should not take glipizide 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 or furosemide
• 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 a 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 glipizide 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 glipizide 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. Glipizide and metformin hydrochloride tablet therapy will need to be stopped temporarily in such instances.

Q14. CAN I TAKE GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS WITH OTHER MEDICATIONS?

Remind your doctor that you are taking glipizide and metformin hydrochloride tablets when any new drug is prescribed or a change is made in how you take a drug already prescribed.

Glipizide and metformin hydrochloride tablets may interfere with the way some drugs work and some drugs may interfere with the action of glipizide and metformin hydrochloride tablets.

Q15. WHAT IF I BECOME PREGNANT WHILE TAKING GLIPIZIDE 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 glipizide 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 glipizide and metformin hydrochloride tablets if you are nursing a child.

Q16. HOW DO I TAKE GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS?

Your doctor will tell you how many glipizide 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 glipizide 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 GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS?

This leaflet is a summary of the most important information about glipizide 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 glipizide 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.