Metamin-GP

Each tablet contains the following colourants: Glimepiride (Metamin-GP) 1 mg: Ferric oxide (red); Glimepiride (Metamin-GP) 2 mg: Ferric oxide (yellow) and lake of indigo carmine.

It also contains the following excipients: Lactose, microcrystalline cellulose, sodium starch glycollate, povidone, crospovidone, purified talc, magnesium stearate and anhydrous colloidal silica.

Metformin hydrochloride (Metamin-GP) is a biguanide antihyperglycemic agent used for treating non-insulin-dependent diabetes mellitus (NIDDM). It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake. Metformin hydrochloride (Metamin-GP) may induce weight loss and is the drug of choice for obese NIDDM patients. Use of Metformin hydrochloride (Metamin-GP) is associated with modest weight loss. When used alone, Metformin hydrochloride (Metamin-GP) does not cause hypoglycemia; however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin. Its main side effects are dyspepsia, nausea and diarrhea. Dose titration and/or use of smaller divided doses may decrease side effects. Metformin hydrochloride (Metamin-GP) should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Metformin hydrochloride (Metamin-GP) decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin hydrochloride (Metamin-GP) may also have a positive effect on lipid levels. In 2012, a combination tablet of linagliptin plus Metformin hydrochloride (Metamin-GP) was marketed under the name Jentadueto for use in patients when treatment with both linagliptin and Metformin hydrochloride (Metamin-GP) is appropriate.

Pioglitazone (Metamin-GP) has been specially formulated with 20 nutrients to help safeguard the daily requirements with particular emphasis on those of special relevance to diabetics. These include vitamins B1, B6 and C, which are important factors in glucose metabolism.

Pioglitazone (Metamin-GP) contains magnesium to help replace that which can be lose through excess excretion and zinc which plays an important role in insulin metabolism and action.

Nutritional Information of Pioglitazone (Metamin-GP): See table.

It does not contain gluten, starch, sugar, fat, salt, yeast, artificial colors and preservatives.

Pioglitazone (Metamin-GP) is a 100% vitamin and mineral supplement capsule.

Pioglitazone hydrochloride (Metamin-GP) has been specially formulated with 20 nutrients to help safeguard the daily requirements with particular emphasis on those of special relevance to diabetics. These include vitamins B1, B6 and C, which are important factors in glucose metabolism.

Pioglitazone hydrochloride (Metamin-GP) contains magnesium to help replace that which can be lose through excess excretion and zinc which plays an important role in insulin metabolism and action.

Nutritional Information of Pioglitazone hydrochloride (Metamin-GP): See table.

It does not contain gluten, starch, sugar, fat, salt, yeast, artificial colors and preservatives.

Pioglitazone hydrochloride (Metamin-GP) is a 100% vitamin and mineral supplement capsule.

Glimepiride (Metamin-GP) tablet 3 mg is used as monotherapy as adjunct to diet and exercise for the management of type II diabetes mellitus (non-insulin-dependent diabetes mellitus) in patients whose blood glucose levels cannot be controlled adequately by diet and exercise alone.

Glimepiride (Metamin-GP) tablet 3 mg also may be used in combination with one or more other oral anti-diabetic agents containing metformin or insulin as adjunct to diet and exercise for the management of type II diabetes mellitus (non-insulin diabetes mellitus) patients whose blood glucose levels cannot be controlled adequately by diet, exercise and oral antidiabetic agent monotherapy.

GLUCOPHAGE (Metformin hydrochloride (Metamin-GP)) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

GLUCOPHAGE XR (Metformin hydrochloride (Metamin-GP)) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Monotherapy and Combination Therapy

Pioglitazone (Metamin-GP) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

Important Limitations of Use

Pioglitazone (Metamin-GP) exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone (Metamin-GP) should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

Use caution in patients with liver disease.

Monotherapy and Combination Therapy

Pioglitazone hydrochloride (Metamin-GP) are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

Important Limitations of Use

Pioglitazone hydrochloride (Metamin-GP) exert their antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone hydrochloride (Metamin-GP) should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

Use caution in patients with liver disease.

Glimepiride (Metamin-GP) is used to treat high blood sugar levels caused by type 2 diabetes. It may be used alone, or in combination with insulin or another oral medicine such as metformin. In type 2 diabetes, insulin produced by the pancreas is not able to get sugar into the cells of the body where it can work properly. Using Glimepiride (Metamin-GP) will help lower blood sugar when it is too high and help restore the way you use food to make energy.. Some people can control type 2 diabetes with diet alone or diet and exercise. Following a specially planned diet and exercising will always be important when you have diabetes, even when you are taking medicines. To work properly, the amount of Glimepiride (Metamin-GP) you take must be balanced against the amount and type of food you eat and the amount of exercise you do. If you change your diet, your exercise, or both, you will want to test your blood sugar to find out if it is too low. Your doctor will teach you what to do if this happens.

Glimepiride (Metamin-GP) is available only with your doctor's prescription.

Metformin hydrochloride (Metamin-GP) is an oral diabetes medicine that helps control blood sugar levels.

Metformin hydrochloride (Metamin-GP) is for people with type 2 diabetes. Metformin hydrochloride (Metamin-GP) is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes.

Metformin hydrochloride (Metamin-GP) may also be used for purposes not listed in this medication guide.

Pioglitazone (Metamin-GP) is an oral diabetes medicine that helps control blood sugar levels.

Pioglitazone (Metamin-GP) is for people with type 2 diabetes. Pioglitazone (Metamin-GP) is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes.

Pioglitazone (Metamin-GP) may also be used for purposes not listed in this medication guide.

Pioglitazone hydrochloride (Metamin-GP) is used to treat a type of diabetes mellitus called type 2 diabetes. It may be used alone or with other medicines such as insulin, Pioglitazone hydrochloride (Metamin-GP), or sulfonylurea agents. Pioglitazone hydrochloride (Metamin-GP) is used together with a proper diet and exercise to help control blood sugar levels. It does this by helping your body use insulin better.

Pioglitazone hydrochloride (Metamin-GP) is available only with your doctor's prescription.

Adults: Recommended Dose: Dosage of Glimepiride (Metamin-GP) must be individualized carefully based on patients' response and tolerance. The lowest effective dosage must be given to patients when used in either as monotherapy or combined with metformin or insulin. Patients should be monitored with regular laboratory evaluations, including glucose levels in blood and urine, to determine therapeutic response and the minimum effective dosage of Glimepiride (Metamin-GP).

Initial

Dosage: The usual initial dose for patients who have not being treated by any other anti-diabetic agents is 1 mg of Glimepiride (Metamin-GP) once daily. The usual initial dose for patients who have received other anti-diabetics agents is 1 mg once daily.

Dosage Titration: If necessary, the daily dose can be increased. Any increase should be based on regular blood glucose level monitoring and should be gradual with adequate intervals of 1-2 weeks, carried out stepwise as 1 mg-2 mg-3 mg-4 mg-6 mg and- in exception cases-8 mg.

Maintenance Dose: The usual maintenance dosage of Glimepiride (Metamin-GP) for the management of type 2 diabetes mellitus ranges from 1-4 mg once daily in patients with well controlled blood glucose levels. Only some patients may benefit from daily dosage of more than 6 mg.

Dose adjustment must also be taken into consideration whenever patients' weight or life-style or other factors which cause an increased susceptibility to hypoglycemia or to an excessive increase in blood glucose levels arise. A timely dose reduction must be considered as the sensitivity to insulin increases along with the improved control of blood glucose level as treatment proceeds in order to avoid hypoglycemia.

Maximum

Dosage: 8 mg once daily only for exceptional cases.

Missed

Dosage: Missed dose must never be corrected by subsequently taking a larger dose.

Duration of Treatment: Treatment with Glimepiride (Metamin-GP) is normally a long-term therapy.

Combination Therapy: Combined therapy with Glimepiride (Metamin-GP) and metformin may be used in patients whose blood glucose levels is not adequately controlled by monotherapy with the maximum dose of either Glimepiride (Metamin-GP) or any of metformin-containing antidiabetic agents. The daily dose of the already taken antidiabetic agent should remain unchanged while the additional medicine should be started from the minimum effective dose and then maybe increased gradually up to the maximum daily dose. Such combination therapy may increase the risk of hypoglycemic reactions. Close medical monitoring should be taken.

Combined therapy with Glimepiride (Metamin-GP) and insulin may be used in patients whose blood glucose level is not adequately controlled by monotherapy with the maximum dose of Glimepiride (Metamin-GP). The daily dose of the Glimepiride (Metamin-GP) should remain unchanged. After starting with low-dose insulin, stepwise upward adjustments of insulin can be done as guided by frequent measurements of fasting blood glucose. Once stable, combination therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily.

Special Populations: Children: Dosing of Glimepiride (Metamin-GP) in children is not recommended since its safety and efficacy has not been established.

Dosing of Glimepiride (Metamin-GP) in patients with adrenal, pituitary, renal or hepatic impairment, debilitated or malnourished patients, geriatric should be conservative to avoid hypoglycemic reactions.

Administration: Glimepiride (Metamin-GP) tablet 3 mg is usually administered orally once daily with breakfast or with the first main meal of the day. Glimepiride (Metamin-GP) tablet 3 mg must be swallowed without chewing and with sufficient amounts of liquid (approximately ½ glass).

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with GLUCOPHAGE or GLUCOPHAGE XR or any other pharmacologic agent. Dosage of GLUCOPHAGE or GLUCOPHAGE XR must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of GLUCOPHAGE is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of GLUCOPHAGE XR in adults is 2000 mg. GLUCOPHAGE should be given in divided doses with meals while GLUCOPHAGE XR should generally be given once daily with the evening meal.

GLUCOPHAGE or GLUCOPHAGE XR should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to GLUCOPHAGE or GLUCOPHAGE XR and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of GLUCOPHAGE or GLUCOPHAGE XR, either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of GLUCOPHAGE or GLUCOPHAGE XR may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

GLUCOPHAGE XR tablets must be swallowed whole and never crushed or chewed.

Occasionally, the inactive ingredients of GLUCOPHAGE XR will be eliminated in the feces as a soft, hydrated mass.

Recommended Dosing Schedule

Adults

In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of GLUCOPHAGE Tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, GLUCOPHAGE may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given 3 times a day with meals.

The usual starting dose of GLUCOPHAGE XR (Metformin hydrochloride (Metamin-GP)) Extended-Release Tablets is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on GLUCOPHAGE XR 2000 mg once daily, a trial of GLUCOPHAGE XR 1000 mg twice daily should be considered. If higher doses of Metformin hydrochloride (Metamin-GP) are required, GLUCOPHAGE should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.

In a randomized trial, patients currently treated with GLUCOPHAGE were switched to GLUCOPHAGE XR. Results of this trial suggest that patients receiving GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from GLUCOPHAGE to GLUCOPHAGE XR, glycemic control should be closely monitored and dosage adjustments made accordingly.

Pediatrics

The usual starting dose of GLUCOPHAGE is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to GLUCOPHAGE or GLUCOPHAGE XR, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Concomitant GLUCOPHAGE Or GLUCOPHAGE XR And

Oral Sulfonylurea Therapy In Adult Patients

If patients have not responded to 4 weeks of the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing GLUCOPHAGE or GLUCOPHAGE XR at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for Metformin hydrochloride (Metamin-GP) plus glyburide (glibenclamide).

With concomitant GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on GLUCOPHAGE 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of GLUCOPHAGE and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c, and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken.

If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without GLUCOPHAGE or GLUCOPHAGE XR.

Concomitant GLUCOPHAGE Or GLUCOPHAGE XR And Insulin Therapy In Adult Patients

The current insulin dose should be continued upon initiation of GLUCOPHAGE or GLUCOPHAGE XR therapy. GLUCOPHAGE or GLUCOPHAGE XR therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of GLUCOPHAGE or GLUCOPHAGE XR should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for GLUCOPHAGE and 2000 mg for GLUCOPHAGE XR. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and GLUCOPHAGE or GLUCOPHAGE XR. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations

GLUCOPHAGE or GLUCOPHAGE XR are not recommended for use in pregnancy. GLUCOPHAGE is not recommended in patients below the age of 10 years. GLUCOPHAGE XR is not recommended in pediatric patients (below the age of 17 years).

The initial and maintenance dosing of GLUCOPHAGE or GLUCOPHAGE XR should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.

How supplied

GLUCOPHAGE® (Metformin hydrochloride (Metamin-GP)) Tablets

GLUCOPHAGE 500 mg tablets are round, white to off-white, film-coated tablets debossed with “BMS 6060” around the periphery of the tablet on one side and “500” debossed across the face of the other side.

GLUCOPHAGE 850 mg tablets are round, white to off-white, film-coated tablets debossed with “BMS 6070” around the periphery of the tablet on one side and “850” debossed across the face of the other side.

GLUCOPHAGE 1000 mg tablets are white, oval, biconvex, film-coated tablets with “BMS 6071” debossed on one side and “1000” debossed on the opposite side and with a bisect line on both sides.

GLUCOPHAGE® XR (Metformin hydrochloride (Metamin-GP)) Extended-Release Tablets

GLUCOPHAGE XR 500 mg tablets are white to off-white, capsule shaped, biconvex tablets, with “BMS 6063” debossed on one side and “500” debossed across the face of the other side.

GLUCOPHAGE XR 750 mg tablets are capsule shaped, biconvex tablets, with “BMS 6064” debossed on one side and “750” debossed on the other side. The tablets are pale red and may have a mottled appearance.

Storage

Store at 20°-25° C (68°-77° F); excursions permitted to 15°-30° C (59°-86° F).

Dispense in light-resistant containers.

Distributed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Revised: June 2015

Recommendations for All Patients

Pioglitazone (Metamin-GP) should be taken once daily and can be taken without regard to meals.

The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.

The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.

The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.

After initiation of Pioglitazone (Metamin-GP) or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure.

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Pioglitazone (Metamin-GP). Routine periodic monitoring of liver tests during treatment with Pioglitazone (Metamin-GP) is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Pioglitazone (Metamin-GP) or who are found to have abnormal liver tests while taking Pioglitazone (Metamin-GP) should be managed as described under WARNINGS AND PRECAUTIONS.

Concomitant Use with an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient co-administered Pioglitazone (Metamin-GP) and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered Pioglitazone (Metamin-GP) and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of Pioglitazone (Metamin-GP) and gemfibrozil, a strong CYP2C8 inhibitor, increases Pioglitazone (Metamin-GP) exposure approximately 3-fold. Therefore, the maximum recommended dose of Pioglitazone (Metamin-GP) is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

How supplied

Dosage Forms And Strengths

Round tablet contains Pioglitazone (Metamin-GP) as follows:

• 15 mg: White to off-white, debossed with “Pioglitazone (Metamin-GP)” on one side and “15” on the other
• 30 mg: White to off-white, debossed with “Pioglitazone (Metamin-GP)” on one side and “30” on the other
• 45 mg: White to off-white, debossed with “Pioglitazone (Metamin-GP)” on one side and “45” on the other

Storage And Handling

Pioglitazone (Metamin-GP) is available in 15 mg, 30 mg, and 45 mg tablets as follows:

15 mg tablet: White to off-white, round, convex, nonscored tablet with “Pioglitazone (Metamin-GP)” on one side, and “15” on the other, available in:

NDC 64764-151-04 Bottles of 30

NDC 64764-151-05 Bottles of 90

NDC 64764-151-06 Bottles of 500

30 mg tablet: White to off-white, round, flat, nonscored tablet with “Pioglitazone (Metamin-GP)” on one side, and “30” on the other, available in:

NDC 64764-301-14 Bottles of 30

NDC 64764-301-15 Bottles of 90

NDC 64764-301-16 Bottles of 500

45 mg tablet: White to off-white, round, flat, nonscored tablet with “Pioglitazone (Metamin-GP)” on one side, and “45” on the other, available in:

NDC 64764-451-24 Bottles of 30

NDC 64764-451-25 Bottles of 90

NDC 64764-451-26 Bottles of 500

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep container tightly closed, and protect from light, moisture and humidity.

Distributed by: Takeda Pharmaceuticals America, Inc., Deerfield, IL 60015. Revised: November 2013

Recommendations for All Patients

Pioglitazone hydrochloride (Metamin-GP) should be taken once daily and can be taken without regard to meals.

The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.

The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.

The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.

After initiation of Pioglitazone hydrochloride (Metamin-GP) or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure.

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Pioglitazone hydrochloride (Metamin-GP). Routine periodic monitoring of liver tests during treatment with Pioglitazone hydrochloride (Metamin-GP) is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Pioglitazone hydrochloride (Metamin-GP) or who are found to have abnormal liver tests while taking Pioglitazone hydrochloride (Metamin-GP) should be managed as described under Warnings and Precautions.

Concomitant Use With an Insulin Secretagogue or Insulin

If hypoglycemia occurs in a patient coadministered Pioglitazone hydrochloride (Metamin-GP) and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered Pioglitazone hydrochloride (Metamin-GP) and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

Concomitant Use With Strong CYP2C8 Inhibitors

Coadministration of Pioglitazone hydrochloride (Metamin-GP) and gemfibrozil, a strong CYP2C8 inhibitor, increases Pioglitazone hydrochloride (Metamin-GP) exposure approximately 3 fold. Therefore, the maximum recommended dose of Pioglitazone hydrochloride (Metamin-GP) is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

See also:
What is the most important information I should know about Glimepiride (Metamin-GP)?

Glimepiride (Metamin-GP) is not suitable for the treatment of insulin-dependent (type I) diabetes mellitus (eg, for the treatment of diabetics with a history of ketoacidosis), of diabetic ketoacidosis, or of diabetic precoma or coma. Glimepiride (Metamin-GP) must not be used in patients hypersensitive to Glimepiride (Metamin-GP), other sulfonylureas, other sulfonamides, or any of the excipients (risk of hypersensitivity reactions).

No experience has been gained concerning the use of Glimepiride (Metamin-GP) in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of renal or hepatic function, a changeover to insulin is indicated, not least to achieve optimal metabolic control.

Use in pregnancy & lactation: To avoid risk of harm to the child, Glimepiride (Metamin-GP) must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician and should changeover to insulin. Ingestion of Glimepiride (Metamin-GP) with the breastmilk may harm the child. Therefore, Glimepiride (Metamin-GP) must not be taken by breastfeeding women. Either a changeover to insulin or a complete discontinuation of breastfeeding is necessary.

See also:
What is the most important information I should know about Metformin hydrochloride (Metamin-GP)?

Metformin hydrochloride (Metamin-GP) extended-release tablets are contraindicated in patients with:

1. 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.

2. Known hypersensitivity to Metformin hydrochloride (Metamin-GP).

3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

Diabetic ketoacidosis should be treated with insulin.

Metformin hydrochloride (Metamin-GP) extended-release 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:
What is the most important information I should know about Pioglitazone (Metamin-GP)?

You should not use this medication if you are allergic to Pioglitazone (Metamin-GP), if you have severe heart failure, if you have active bladder cancer, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Do not take Pioglitazone (Metamin-GP) for longer than recommended. Taking this medication for longer than 1 year (12 months) may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Before taking Pioglitazone (Metamin-GP), tell your doctor if you have congestive heart failure or heart disease, fluid retention, a history of bladder cancer, a history of heart attack or stroke, or liver disease.

Take care not to let your blood sugar get too low. Low blood sugar (hypoglycemia) can occur if you skip a meal, exercise too long, drink alcohol, or are under stress. Symptoms include headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating. Carry hard candy or glucose tablets with you in case you have low blood sugar. Other sugar sources include orange juice and milk. Be sure your family and close friends know how to help you in an emergency.

Some women using Pioglitazone (Metamin-GP) have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

Women may also be more likely than men to have bone fractures in the upper arm, hand, or foot while taking Pioglitazone (Metamin-GP). Talk with your doctor if you are concerned about this possibility.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with Pioglitazone (Metamin-GP).

See also:
What is the most important information I should know about Pioglitazone hydrochloride (Metamin-GP)?

Use Glimepiride (Metamin-GP) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Glimepiride (Metamin-GP) by mouth with breakfast or the first main meal of the day unless your doctor tells you otherwise.
• Glimepiride (Metamin-GP) works best if it is taken at the same time each day.
• Continue to take Glimepiride (Metamin-GP) even if you feel well. Do not miss any doses.
• If you miss a dose of Glimepiride (Metamin-GP), take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Glimepiride (Metamin-GP).

Use Metformin hydrochloride (Metamin-GP) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Metformin hydrochloride (Metamin-GP). Talk to your pharmacist if you have questions about this information.
• Take Metformin hydrochloride (Metamin-GP) by mouth with the evening meal unless your doctor tells you otherwise.
• Swallow Metformin hydrochloride (Metamin-GP) whole. Do not break, crush, or chew before swallowing.
• Take Metformin hydrochloride (Metamin-GP) on a regular schedule to get the most benefit from it. Taking Metformin hydrochloride (Metamin-GP) at the same time each day will help you remember to take it.
• Continue to take Metformin hydrochloride (Metamin-GP) even if you feel well. Do not miss any doses.
• If you miss a dose of Metformin hydrochloride (Metamin-GP), take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Metformin hydrochloride (Metamin-GP).

Use Pioglitazone (Metamin-GP) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Pioglitazone (Metamin-GP) comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Pioglitazone (Metamin-GP) refilled.
• Take Pioglitazone (Metamin-GP) by mouth with or without food.
• Continue to take Pioglitazone (Metamin-GP) even if you feel well. Do not miss any doses.
• Taking Pioglitazone (Metamin-GP) at the same time each day will help you remember to take it.
• If you miss a dose of Pioglitazone (Metamin-GP), skip the missed dose and go back to your regular dosing schedule, unless your doctor directs you otherwise. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Pioglitazone (Metamin-GP).

Use Pioglitazone hydrochloride (Metamin-GP) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Pioglitazone hydrochloride (Metamin-GP) comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Pioglitazone hydrochloride (Metamin-GP) refilled.
• Take Pioglitazone hydrochloride (Metamin-GP) by mouth with or without food.
• Continue to take Pioglitazone hydrochloride (Metamin-GP) even if you feel well. Do not miss any doses.
• Taking Pioglitazone hydrochloride (Metamin-GP) at the same time each day will help you remember to take it.
• If you miss a dose of Pioglitazone hydrochloride (Metamin-GP), skip the missed dose and go back to your regular dosing schedule, unless your doctor directs you otherwise. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Pioglitazone hydrochloride (Metamin-GP).

Glimepiride (Metamin-GP) is used to lower the blood sugar levels in type 2 diabetes mellitus when diet, physical exercise and weight reduction alone are not adequate.

Use: Labeled Indications

Diabetes mellitus, type 2: Management of type 2 diabetes mellitus when hyperglycemia cannot be managed with diet and exercise alone.

Note: If not contraindicated and if tolerated, Metformin hydrochloride (Metamin-GP) is the preferred initial pharmacologic agent for type 2 diabetes management (ADA 2020).

Off Label Uses

Antipsychotic-induced weight gain

Data from multiple meta-analyses of randomized controlled trials with varying degrees of heterogeneity (primarily in patients with schizophrenia and schizoaffective disorder) support the use of Metformin hydrochloride (Metamin-GP) in promoting modest weight loss and preventing weight gain associated with second-generation antipsychotics in adult patients

Pioglitazone (Metamin-GP) is an anti-diabetic drug (thiazolidinedione-type, also called "glitazones") used along with a proper diet and exercise program to control high blood sugar in patients with type 2 diabetes. It works by helping to restore your body's proper response to insulin, thereby lowering your blood sugar.

Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.

Pioglitazone (Metamin-GP) is used either alone or in combination with other anti-diabetic medications (such as Pioglitazone (Metamin-GP) or a sulfonylurea such as glyburide).

Talk to your doctor about the risks and benefits of Pioglitazone (Metamin-GP).

How to use Pioglitazone (Metamin-GP)

Read the Medication Guide provided by your pharmacist before you start using Pioglitazone (Metamin-GP) and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually once daily. Dosage is based on your medical condition, response to treatment, and if you are taking other anti-diabetic drugs. Your doctor will adjust your dose based on your blood sugar levels to find the best dose for you. Follow your doctor's directions carefully.

Take this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day.

If you are already taking another anti-diabetic drug (such as Pioglitazone (Metamin-GP) or a sulfonylurea), follow your doctor's directions carefully for stopping/continuing the old drug and starting this medication. Carefully follow the medication treatment plan, meal plan, and exercise program your doctor has recommended.

Check your blood sugar regularly as directed by your doctor. Keep track of the results, and share them with your doctor. Tell your doctor if your blood sugar measurements are too high or too low. Your dosage/treatment may need to be changed. It may take up to 2 to 3 months before the full benefit of this drug takes effect.

Pioglitazone hydrochloride (Metamin-GP) is an anti-diabetic drug (thiazolidinedione-type, also called "glitazones") used along with a proper diet and exercise program to control high blood sugar in patients with type 2 diabetes. It works by helping to restore your body's proper response to insulin, thereby lowering your blood sugar.

Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.

Pioglitazone hydrochloride (Metamin-GP) is used either alone or in combination with other anti-diabetic medications (such as Pioglitazone hydrochloride (Metamin-GP) or a sulfonylurea such as glyburide).

Talk to your doctor about the risks and benefits of Pioglitazone hydrochloride (Metamin-GP).

How to use Pioglitazone hydrochloride (Metamin-GP)

Read the Medication Guide provided by your pharmacist before you start using Pioglitazone hydrochloride (Metamin-GP) and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually once daily. Dosage is based on your medical condition, response to treatment, and if you are taking other anti-diabetic drugs. Your doctor will adjust your dose based on your blood sugar levels to find the best dose for you. Follow your doctor's directions carefully.

Take this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day.

If you are already taking another anti-diabetic drug (such as Pioglitazone hydrochloride (Metamin-GP) or a sulfonylurea), follow your doctor's directions carefully for stopping/continuing the old drug and starting this medication. Carefully follow the medication treatment plan, meal plan, and exercise program your doctor has recommended.

Check your blood sugar regularly as directed by your doctor. Keep track of the results, and share them with your doctor. Tell your doctor if your blood sugar measurements are too high or too low. Your dosage/treatment may need to be changed. It may take up to 2 to 3 months before the full benefit of this drug takes effect.

See also:
What other drugs will affect Glimepiride (Metamin-GP)?

Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require Glimepiride (Metamin-GP) dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.

The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including Glimepiride (Metamin-GP), increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving Glimepiride (Metamin-GP), monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving Glimepiride (Metamin-GP), monitor the patient closely for worsening glycemic control.

The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including Glimepiride (Metamin-GP), leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving Glimepiride (Metamin-GP), monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving Glimepiride (Metamin-GP), monitor the patient closely for hypoglycemia.

Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of Glimepiride (Metamin-GP)'s glucose-lowering effect.

Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of Glimepiride (Metamin-GP) in an unpredictable fashion.

The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

Miconazole

A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.

Cytochrome P450 2C9 Interactions

There may be an interaction between Glimepiride (Metamin-GP) and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of Glimepiride (Metamin-GP), causing increased plasma concentrations of Glimepiride (Metamin-GP) which may lead to hypoglycemia. Rifampin may induce the metabolism of Glimepiride (Metamin-GP), causing decreased plasma concentrations of Glimepiride (Metamin-GP) which may lead to worsening glycemic control.

Concomitant Administration Of Colesevelam

Colesevelam can reduce the maximum plasma concentration and total exposure of Glimepiride (Metamin-GP) when the two are coadministered. However, absorption is not reduced when Glimepiride (Metamin-GP) is administered 4 hours prior to colesevelam. Therefore, Glimepiride (Metamin-GP) should be administered at least 4 hours prior to colesevelam.

See also:
What other drugs will affect Metformin hydrochloride (Metamin-GP)?

(Clinical Evaluation of Drug Interactions Conducted with GLUCOPHAGE)

Glyburide

In a single-dose interaction study in type 2 diabetes patients, coadministration of Metformin hydrochloride (Metamin-GP) and glyburide did not result in any changes in either Metformin hydrochloride (Metamin-GP) pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain;">Sulfonylurea Therapy in Adult Patients).

Furosemide

A single-dose, Metformin hydrochloride (Metamin-GP)-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the Metformin hydrochloride (Metamin-GP) plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in Metformin hydrochloride (Metamin-GP) renal clearance. When administered with Metformin hydrochloride (Metamin-GP), the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance.

See also:
What other drugs will affect Pioglitazone (Metamin-GP)?

Oral Contraceptives:

Insulin or Insulin Secretagogues: The dose of insulin and insulin secretagogues (eg, sulfonylurea) should be reduced since concomitant administration may result in hypoglycemia.

Midazolam: Administration of Pioglitazone (Metamin-GP) for 15 days followed by a 7.5 mg single dose of midazolam syrup resulted in a 26% reduction in midazolam C_max and AUC.

Strong CYP2C8 Inhibitors: Gemfibrozil (an inhibitor of CYP450 2C8) resulted in a 3-fold increase in the plasma concentration of parent Pioglitazone (Metamin-GP) and also inhibited the further metabolism of M-III and M-IV. Careful blood glucose monitoring and dosage adjustments are suggested during co-administration of Pioglitazone (Metamin-GP) and gemfibrozil. If used in combination with gemfibrozil or other strong CYP2C8 inhibitors, a maximum dose of Pioglitazone (Metamin-GP) 15 mg should be used.

CYP2C8 Inducers: Co-administration of Pioglitazone (Metamin-GP) with rifampicin (an inducer of CYP450 2C8) resulted in a 54% reduction in Pioglitazone (Metamin-GP)'s AUC. The dose of Pioglitazone (Metamin-GP) may need to be increased when rifampicin is co-administered and glycemic control closely monitored.

If an inducer of CYP2C8 is started or stopped during treatment with Pioglitazone (Metamin-GP), the maximum recommended dose of 45 mg should not be exceeded and changes in diabetes treatment may be needed based on the patient's clinical response.

Drugs Metabolized via Cytochrome P-450: The cytochrome P-450 isoform, CYP3A4, is partially responsible for the metabolism of Pioglitazone (Metamin-GP). Potential pharmacokinetic interaction (reduction in C_max and AUC) with CYP3A4 substrates (eg, atorvastatin, nifedipine). Clinical significance of this finding is unknown.

Peak plasma concentration and area under the AUC of Pioglitazone (Metamin-GP) may increase when taken concomitantly with CYP3A4 inhibitors eg, ketoconazole. However, pharmacokinetic interaction is unlikely with ranitidine which is a relatively weak CYP3A4 inhibitor.

In vitro studies have shown no inhibition of any subtype of cytochrome P-450. Interactions with substances metabolized by these enzymes are unlikely: Ciclosporin, calcium channel blockers, and HMGCoA reductase inhibitors.

Co-administration of Pioglitazone (Metamin-GP) with the following drugs did not show pharmacokinetic interactions: Pioglitazone (Metamin-GP), glipizide, digoxin, phenprocoumon, fexofenadine, CYP2C9 substrates (eg, warfarin), CYP1A2 substrates (eg, theophylline).

See also:
What other drugs will affect Pioglitazone hydrochloride (Metamin-GP)?

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

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

CYP2C8 Inducers (Moderate): May decrease the serum concentration of Pioglitazone hydrochloride (Metamin-GP). Monitor therapy

CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Pioglitazone hydrochloride (Metamin-GP). Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Pioglitazone hydrochloride (Metamin-GP). Management: Limit the Pioglitazone hydrochloride (Metamin-GP) dose to 15 mg daily and monitor for increased Pioglitazone hydrochloride (Metamin-GP) toxicities (eg, hypoglycemia) when used in combination with strong CYP2C8 inhibitors. Consider therapy modification

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

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

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

Insulins: Pioglitazone hydrochloride (Metamin-GP) may enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with Pioglitazone hydrochloride (Metamin-GP), dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

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

Pregabalin: May enhance the fluid-retaining effect of Thiazolidinediones. Monitor therapy

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

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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

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

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

Sulfonylureas: Thiazolidinediones may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

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

Topiramate: May decrease the serum concentration of Pioglitazone hydrochloride (Metamin-GP). Monitor therapy

See also:
What are the possible side effects of Glimepiride (Metamin-GP)?

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:

• Hypoglycemia
• Hemolytic anemia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Approximately 2,800 patients with type 2 diabetes have been treated with Glimepiride (Metamin-GP) in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with Glimepiride (Metamin-GP) for at least 1 year.

Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebocontrolled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among Glimepiride (Metamin-GP)-treated patients and more commonly than in patients who received placebo.

Table 1. Eleven Pooled Placebo-Controlled Trials ranging from 13 weeks to 12 months : Adverse Events (Excluding Hypoglycemia) Occurring in ≥5% of Glimepiride (Metamin-GP)-treated Patients and at a Greater Incidence than with Placebo*

Hypoglycemia

In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to Glimepiride (Metamin-GP) 1 mg, 4 mg, 8 mg or placebo. Patients randomized to Glimepiride (Metamin-GP) 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for Glimepiride (Metamin-GP) 1 mg, 17% for Glimepiride (Metamin-GP) 4 mg, 16% for Glimepiride (Metamin-GP) 8 mg and 0% for placebo. All of these events were self-treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg Glimepiride (Metamin-GP) or placebo daily. The dose of Glimepiride (Metamin-GP) was titrated to a target fasting plasma glucose of 90–150 mg/dL. Final daily doses of Glimepiride (Metamin-GP) were 1, 2, 3, 4, 6 or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for Glimepiride (Metamin-GP) vs. placebo was 19.7% vs. 3.2%. All of these events were selftreated.

Weight Gain

Glimepiride (Metamin-GP), like all sulfonylureas, can cause weight gain.

Allergic Reactions

In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of Glimepiride (Metamin-GP)-treated patients. These may resolve despite continued treatment with Glimepiride (Metamin-GP). There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock).

Laboratory Tests

Elevated Serum Alanine Aminotransferase (ALT)

In 11 pooled placebo-controlled trials of Glimepiride (Metamin-GP), 1.9% of Glimepiride (Metamin-GP)-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.

Postmarketing Experience

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

• Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome
• Hemolytic anemia in patients with and without G6PD deficiency
• Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
• Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
• Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia
• Thrombocytopenia (including severe cases with platelet count less than 10,000/μL) and thrombocytopenic purpura
• Hepatic porphyria reactions and disulfiram-like reactions
• Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone
• Dysgeusia
• Alopecia

See also:
What are the possible side effects of Metformin hydrochloride (Metamin-GP)?

In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with Metformin hydrochloride (Metamin-GP) extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered Metformin hydrochloride (Metamin-GP) extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin hydrochloride (Metamin-GP) extended-release tablets patients, and that were more common in Metformin hydrochloride (Metamin-GP) extended-release tablets- than placebo-treated patients, are listed in Table 10.

*Reactions that were more common in Metformin hydrochloride (Metamin-GP) extended-release tablets than placebo-treated patients.

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Metformin hydrochloride (Metamin-GP) extended-release tablets. Additionally, the following adverse reactions were reported in ≥1.0% - ≤5.0% of Metformin hydrochloride (Metamin-GP) extended-release tablets patients and were more commonly reported with Metformin hydrochloride (Metamin-GP) extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

See also:
What are the possible side effects of Pioglitazone (Metamin-GP)?

The following serious adverse reactions are discussed elsewhere in the labeling:

• Congestive heart failure
• Edema
• Fractures

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Over 8500 patients with type 2 diabetes have been treated with Pioglitazone (Metamin-GP) in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with Pioglitazone (Metamin-GP) in the PROactive clinical trial. In these trials, over 6000 patients have been treated with Pioglitazone (Metamin-GP) for six months or longer, over 4500 patients have been treated with Pioglitazone (Metamin-GP) for one year or longer, and over 3000 patients have been treated with Pioglitazone (Metamin-GP) for at least two years.

In six pooled 16-to 26-week placebo-controlled monotherapy and 16-to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with Pioglitazone (Metamin-GP) and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with Pioglitazone (Metamin-GP) than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with Pioglitazone (Metamin-GP) and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with Pioglitazone (Metamin-GP) and 0.6% of patients treated with placebo.

Common Adverse Events: 16-to 26-Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16-to 26-week placebo-controlled monotherapy trials of Pioglitazone (Metamin-GP) is provided in Table 1. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with Pioglitazone (Metamin-GP) than in patients who received placebo. None of these adverse events were related to Pioglitazone (Metamin-GP) dose.

Table 1: Three Pooled 16-to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone (Metamin-GP) Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in Patients Treated with Pioglitazone (Metamin-GP) than in Patients Treated with Placebo

Common Adverse Events: 16-to 24-Week Add-on Combination Therapy Trials

A summary of the overall incidence and types of common adverse events reported in trials of Pioglitazone (Metamin-GP) add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of Pioglitazone (Metamin-GP).

Table 2: 16-to 24-Week Clinical Trials of Pioglitazone (Metamin-GP) Add-on to Sulfonylurea

A summary of the overall incidence and types of common adverse events reported in trials of Pioglitazone (Metamin-GP) add-on to Pioglitazone (Metamin-GP) is provided in Table 3. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of Pioglitazone (Metamin-GP).

Table 3: 16-to 24-Week Clinical Trials of Pioglitazone (Metamin-GP) Add-on to Pioglitazone (Metamin-GP)

Table 4 summarizes the incidence and types of common adverse events reported in trials of Pioglitazone (Metamin-GP) add-on to insulin. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of Pioglitazone (Metamin-GP).

Table 4: 16-to 24-Week Clinical Trials of Pioglitazone (Metamin-GP) Add-on to Insulin

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with Pioglitazone (Metamin-GP) than in patients who received placebo.

Table 5: PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients Treated with Pioglitazone (Metamin-GP) and More Commonly than Placebo

Congestive Heart Failure

A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16-to 24-week add-on to sulfonylurea trials, for the 16-to 24-week add-on to insulin trials, and for the 16-to 24-week add-on to Pioglitazone (Metamin-GP) trials. None of the events were fatal.

Table 6: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either Pioglitazone (Metamin-GP) at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.

Table 7: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone (Metamin-GP) or Glyburide

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.

Table 8: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to Pioglitazone (Metamin-GP) (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of Pioglitazone (Metamin-GP) on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with Pioglitazone (Metamin-GP) and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between Pioglitazone (Metamin-GP) and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with Pioglitazone (Metamin-GP). The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

Table 9: PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

Weight Gain

Dose-related weight gain occurs when Pioglitazone (Metamin-GP) is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 10 and 11 summarize the changes in body weight with Pioglitazone (Metamin-GP) and placebo in the 16-to 26-week randomized, double-blind monotherapy and 16-to 24-week combination add-on therapy trials and in the PROactive trial.

Table 10: Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials

Table 11: Median Change in Body Weight in Patients Treated with Pioglitazone (Metamin-GP) Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial

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Edema

Edema induced from taking Pioglitazone (Metamin-GP) is reversible when Pioglitazone (Metamin-GP) is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of Pioglitazone (Metamin-GP) is provided in Table 12.

Table 12: Adverse Events of Edema in Patients Treated with Pioglitazone (Metamin-GP)

Table 13: Adverse Events of Edema in Patients in the PROactive Trial

Hepatic Effects

There has been no evidence of induced hepatotoxicity with Pioglitazone (Metamin-GP) in the Pioglitazone (Metamin-GP) controlled clinical trial database to date. One randomized, double-blind 3-year trial comparing Pioglitazone (Metamin-GP) to glyburide as add-on to Pioglitazone (Metamin-GP) and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with Pioglitazone (Metamin-GP) and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with Pioglitazone (Metamin-GP) in the Pioglitazone (Metamin-GP) controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the Pioglitazone (Metamin-GP) clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with Pioglitazone (Metamin-GP) 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with Pioglitazone (Metamin-GP) 15 mg, 15.4% with Pioglitazone (Metamin-GP) 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with Pioglitazone (Metamin-GP) 45 mg compared to Pioglitazone (Metamin-GP) 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving Pioglitazone (Metamin-GP) 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving Pioglitazone (Metamin-GP) 45 mg in combination with sulfonylurea (n=2) or Pioglitazone (Metamin-GP) 30 mg or 45 mg in combination with insulin (n=12).

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which Pioglitazone (Metamin-GP) was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pioglitazone (Metamin-GP) compared to 5/3679 (0.14%) in patients not taking Pioglitazone (Metamin-GP). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pioglitazone (Metamin-GP) and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.

Laboratory Abnormalities

Hematologic Effects

Pioglitazone (Metamin-GP) may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with Pioglitazone (Metamin-GP) compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with Pioglitazone (Metamin-GP) therapy and are not likely to be associated with any clinically significant hematologic effects.

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in Pioglitazone (Metamin-GP) clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with Pioglitazone (Metamin-GP) (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive Pioglitazone (Metamin-GP), two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued Pioglitazone (Metamin-GP) due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to Pioglitazone (Metamin-GP) therapy is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pioglitazone (Metamin-GP). 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.

• New onset or worsening diabetic macular edema with decreased visual acuity.
• Fatal and nonfatal hepatic failure.

Postmarketing reports of congestive heart failure have been reported in patients treated with Pioglitazone (Metamin-GP), both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.

See also:
What are the possible side effects of Pioglitazone hydrochloride (Metamin-GP)?

The following serious adverse reactions are discussed elsewhere in the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Over 8500 patients with type 2 diabetes have been treated with Pioglitazone hydrochloride (Metamin-GP) in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with Pioglitazone hydrochloride (Metamin-GP) in the PROactive clinical trial. In these trials, over 6000 patients have been treated with Pioglitazone hydrochloride (Metamin-GP) for six months or longer, over 4500 patients have been treated with Pioglitazone hydrochloride (Metamin-GP) for one year or longer, and over 3000 patients have been treated with Pioglitazone hydrochloride (Metamin-GP) for at least two years.

In six pooled 16 to 26 week placebo-controlled monotherapy and 16 to 24 week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with Pioglitazone hydrochloride (Metamin-GP) and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with Pioglitazone hydrochloride (Metamin-GP) than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with Pioglitazone hydrochloride (Metamin-GP) and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with Pioglitazone hydrochloride (Metamin-GP) and 0.6% of patients treated with placebo.

Common Adverse Events: 16 to 26 Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of Pioglitazone hydrochloride (Metamin-GP) is provided in Table 1. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with Pioglitazone hydrochloride (Metamin-GP) than in patients who received placebo. None of these adverse events were related to Pioglitazone hydrochloride (Metamin-GP) dose.

Common Adverse Events: 16 to 24 Week Add-on Combination Therapy Trials

A summary of the overall incidence and types of common adverse events reported in trials of Pioglitazone hydrochloride (Metamin-GP) add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of Pioglitazone hydrochloride (Metamin-GP).

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

A summary of the overall incidence and types of common adverse events reported in trials of Pioglitazone hydrochloride (Metamin-GP) add-on to Pioglitazone hydrochloride (Metamin-GP) is provided in Table 3. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of Pioglitazone hydrochloride (Metamin-GP).

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

Table 4 summarizes the incidence and types of common adverse events reported in trials of Pioglitazone hydrochloride (Metamin-GP) add-on to insulin. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of Pioglitazone hydrochloride (Metamin-GP).

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with Pioglitazone hydrochloride (Metamin-GP) than in patients who received placebo.

Mean duration of patient follow-up was 34.5 months.

Congestive Heart Failure

A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16 to 24 week add-on to sulfonylurea trials, for the 16 to 24 week add-on to insulin trials, and for the 16 to 24 week add-on to Pioglitazone hydrochloride (Metamin-GP) trials. None of the events were fatal.

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either Pioglitazone hydrochloride (Metamin-GP) at daily doses of 30 mg to 45 mg (n = 262) or glyburide at daily doses of 10 mg to 15 mg (n = 256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to Pioglitazone hydrochloride (Metamin-GP) (N = 2605), force-titrated up to 45 mg daily or placebo (N = 2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of Pioglitazone hydrochloride (Metamin-GP) on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with Pioglitazone hydrochloride (Metamin-GP) and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p = 0.10).

Although there was no statistically significant difference between Pioglitazone hydrochloride (Metamin-GP) and placebo for the three year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with Pioglitazone hydrochloride (Metamin-GP). The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

CABG = coronary artery bypass grafting; PCI = percutaneous intervention

Weight Gain

Dose-related weight gain occurs when Pioglitazone hydrochloride (Metamin-GP) is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 10 and 11 summarize the changes in body weight with Pioglitazone hydrochloride (Metamin-GP) and placebo in the 16 to 26 week randomized, double-blind monotherapy and 16 to 24 week combination add-on therapy trials and in the PROactive trial.

Note: Median exposure for both Pioglitazone hydrochloride (Metamin-GP) and Placebo was 2.7 years.

Edema

Edema induced from taking Pioglitazone hydrochloride (Metamin-GP) is reversible when Pioglitazone hydrochloride (Metamin-GP) is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of Pioglitazone hydrochloride (Metamin-GP) is provided in Table 12.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

Hepatic Effects

There has been no evidence of induced hepatotoxicity with Pioglitazone hydrochloride (Metamin-GP) in the Pioglitazone hydrochloride (Metamin-GP) controlled clinical trial database to date. One randomized, double-blind 3 year trial comparing Pioglitazone hydrochloride (Metamin-GP) to glyburide as add-on to Pioglitazone hydrochloride (Metamin-GP) and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with Pioglitazone hydrochloride (Metamin-GP) and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with Pioglitazone hydrochloride (Metamin-GP) in the Pioglitazone hydrochloride (Metamin-GP) controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the Pioglitazone hydrochloride (Metamin-GP) clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16 week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with Pioglitazone hydrochloride (Metamin-GP) 30 mg and 0.5% with placebo. In the 16 week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with Pioglitazone hydrochloride (Metamin-GP) 15 mg, 15.4% with Pioglitazone hydrochloride (Metamin-GP) 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with Pioglitazone hydrochloride (Metamin-GP) 45 mg compared to Pioglitazone hydrochloride (Metamin-GP) 30 mg in both the 24 week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24 week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving Pioglitazone hydrochloride (Metamin-GP) 30 mg (0.9%) in the 24 week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization. These patients were receiving Pioglitazone hydrochloride (Metamin-GP) 45 mg in combination with sulfonylurea (n = 2) or Pioglitazone hydrochloride (Metamin-GP) 30 mg or 45 mg in combination with insulin (n = 12).

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which Pioglitazone hydrochloride (Metamin-GP) was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pioglitazone hydrochloride (Metamin-GP) compared to 5/3679 (0.14%) in patients not taking Pioglitazone hydrochloride (Metamin-GP). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pioglitazone hydrochloride (Metamin-GP) and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.

Laboratory Abnormalities

Hematologic Effects

Pioglitazone hydrochloride (Metamin-GP) may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with Pioglitazone hydrochloride (Metamin-GP) compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with Pioglitazone hydrochloride (Metamin-GP) therapy and are not likely to be associated with any clinically significant hematologic effects.

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in Pioglitazone hydrochloride (Metamin-GP) clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with Pioglitazone hydrochloride (Metamin-GP) (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive Pioglitazone hydrochloride (Metamin-GP), two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued Pioglitazone hydrochloride (Metamin-GP) due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to Pioglitazone hydrochloride (Metamin-GP) therapy is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pioglitazone hydrochloride (Metamin-GP). 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.

Postmarketing reports of congestive heart failure have been reported in patients treated with Pioglitazone hydrochloride (Metamin-GP), both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.