<p><strong>General</strong>: Due to the mechanisms of action, Pioglitazone is active only in the presence of endogenous insulin. Therefore, combination&nbsp;of Pioglitazone and Glimepiride should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.<br />
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<strong>Hypoglycemia:</strong>&nbsp;All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic&nbsp;action of glucose lowering drugs. Debilitated or malnourished patients and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs.<br />
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<strong>Loss of Control of Blood Glucose</strong>: When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold combination of Pioglitazone and Glimepiride and temporarily administer insulin. Combination of Pioglitazone and Glimepiride may be reinstituted after the acute episode is resolved.<br />
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<strong>Edema</strong>: Combination of Pioglitazone and Glimepiride should be used with caution in patients with edema. Since thiazolidinediones, including Pioglitazone can cause fluid retention, which can exacerbate or lead to congestive heart failure,&nbsp;combination of Pioglitazone and Glimepiride should be used with caution in patients at risk for heart failure.<br />
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<strong>Weight Gain</strong>: Dose-related weight gain was seen with Pioglitazone alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.<br />
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<strong>Hepatic Effects</strong>: Liver enzymes should be checked prior to the initiation of therapy with combination of Pioglitazone and Glimepiride in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with combination of Pioglitazone and Glimepiride should not be initiated in patients with increased baseline liver enzyme levels (ALT &gt;2.5X upper limit of normal). If at any time ALT levels increase to &gt;3X the upper limit of normal in patients on therapy with&nbsp;combination of Pioglitazone and Glimepiride, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain &gt;3X the upper limit of normal, therapy with combination of Pioglitazone and Glimepiride should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, and anorexia, and/or dark urine, liver enzymes should be checked.</p>