ZOLIGET Tablet

As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with glimepiride alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.

Dosage & Administration

General

The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia.

Dosage Recommendations

Selecting the starting dose should be based on the patient’s current regimen of pioglitazone and /or sulfonylurea.

Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. It is recommended that a single dose of ZOLIGET be administered once daily with the first main meal.

Starting dose for patients currently on pioglitazone monotherapy

Based on the usual starting doses of glimepiride (1mg or 2mg once daily), and pioglitazone 15mg or 30mg, ZOLIGET may be initiated at 30mg+2mg once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients currently on glimepiride monotherapy

Based on the usual starting dose of pioglitazone (15mg or 30mg daily).ZOLIGET may be initiated at 30mg+2mg or 30mg+4mg once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients switching from combination therapy of pioglitazone plus glimepiride as separate tablets

ZOLIGET may be initiated with 30mg+2mg or 30mg+4mg based on the dose of pioglitazone and glimepiride already being taken. Patients who are not controlled with 15mg of pioglitazone in combination with glimepiride should be carefully monitored when switched to ZOLIGET.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulphonylurea

No exact dosage relationship exists between glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2mg glimepiride, ZOLIGET should be limited initially to a starting dose of 30mg+2mg once daily, and adjusted after assessing adequacy of therapeutic response. Any change in diabetic therapy should be undertaken with care and appropriate monitoring as change in glycemic control can occur. Patients should be observed carefully for hypoglycemia (1-2 weeks), especially from longer half-life sulphonylureas due to potential overlapping of drug effect.

Maximum Recommended Dose

ZOLIGET tablets are available as a 30mg pioglitazone plus 2mg glimepiride or a 30mg pioglitazone plus 4mg glimepiride formulation for oral administration. The maximum recommended daily dose for pioglitazone is 45mg and the maximum recommended daily dose for glimepiride is 8mg. ZOLIGET should therefore not be given more than once daily at any of the tablet strengths.

Special Patient Populations

- In elderly

- Malnourished patients

- In patients with renal or hepatic insufficiency

- Patient exhibits clinical evidence of active liver disease or increased serum transaminase levels

- Patients with type 2 diabetes and systolic dysfunction

In patients

- with known hypersensitivity to pioglitazone, glimepiride or any other component of the product.

- with diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

- with antihypertensive effect in the presence of insulin; therefore this drug should not be used in patients of type 1 diabetes or for the treatment of diabetic ketoacidosis.

- with moderate to severe heart failure or liver problems.

The most common side effects for the combination are anxiety, bladder pain, bloody or cloudy urine, blurred vision, chills, cold sweats, coma, confusion, cool pale skin, depression, difficult/burning or painful urination, fast heartbeat, frequent urge to urinate, headache, increased hunger, increased weight, lower back or side pain, nausea, nervousness, nightmares, seizures, shakiness, slurred speech, swelling of feet or lower legs, unusual tiredness or weakness cough, ear congestion, hoarseness, joint pain, loss of voice, nasal congestion , tooth disorder, voice changes.

The less common side effects for the combination include accidental injury, loss of appetite, pain or swelling in arms or legs without any injury, pale skin, stomach pain, troubled breathing with exertion, unusual bleeding or bruising, vomiting, weight low, yellow eyes or skin, allergic skin reactions.

Other side effects include upper respiratory tract infection, myalgia, diabetes aggravated, asthenia. In isolated cases, impairment of liver function (e.g. with cholestasis and jaundice) as well as hepatitis, which may also lead to liver failure have been reported. Cases of hyponatremia have been reported most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The hematologic adverse reactions include leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia and pancytopenia.

See the package insert about the details below:

- Pioglitazone Hydrochloride

- Gemfibrozil & Rifampin

- Ketoconazole

- Atorvastatin Calcium

- Midazolam

Glimepiride

- General: The hypoglycemic action of sulphonylureas may be potentiated by certain drugs, including NSAIDs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for hypoglycemia when these drugs are co-administered. Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for loss of glycemic control when these drugs are co-administered.

- Propanolol

- Miconazole

This medication is not recommended for use in pregnancy, nursing mothers and in pediatric patients.

Warnings

CONGESTIVE HEART FAILURE

- Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of ZOLIGET, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation of ZOLIGET must be considered.

- ZOLIGET is not recommended in patients with symptomatic heart failure, initiation of ZOLIGET in patients with established NYHA ClassⅢorⅣheart failure is contraindicated.

PRECAUTIONS

- Pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered.

- All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Debilitated patients, malnourished patients and patients with adrenal, pituitary, renal or hepatic insufficiency are particularly susceptible to the hypoglycemic action of sulfonylureas and should therefore be carefully monitored. The dosage glimepiride should be carefully monitored. The dosage of glimepiride should be carefully adjusted in these patients.

- Pioglitazone may cause decline in hematocrit value along with the decline in mean hemoglobin values by 2%25-4% causing anemia. These changes primarily occurred within the first 4-12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematological clinical effects.

- In patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture in female patients taking pioglitazone is observed. The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

- Alcohol ingestion, severe or prolonged exercise, deficient caloric intake or use of more than one antidiabetic agent may predispose patients to the development of hypoglycemia.

- When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. As such times, it may be necessary to add insulin in combination with glimepiride or even use insulin monotherapy.

- The patient’s fasting blood glucose and HbA1c must be measured periodically to determine the minimum effective dose of pioglitazone + glimepiride combination for the patient.

- Liver enzyme monitoring is recommended prior to initiation of therapy with pioglitazone + glimepiride combination in all patients and periodically thereafter per the clinical judgment of the health care professional.

ZOLIGET is a combination of two antihyperglycemic agents to improve glycemic control in patients with type 2 diabetes.

Pioglitazone

Pioglitazone is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARɤ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARɤ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

Glimepiride

The primary mechanism of action of glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects (e.g., reduction of basal hepatic glucose production and increased peripheral tissue sensitivity to insulin and glucose uptake) may also play a role in the activity of glimepiride. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.