Pioglitazone + Glimepiride

This is indicated as an adjunct to diet and exercise as a once-daily combination therapy 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 a sulfonylurea alone, or for those patients who have initially responded to Pioglitazone alone and require additional glycemic control.

Pioglitazone & Glimepiride combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Pioglitazone, a member of the thiazolidinedione class, and Glimepiride, a member of the sulfonylurea class.

Pioglitazone is an insulin-sensitizing agent that acts primarily by enhancing peripheral glucose utilization. It 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 disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

The primary mechanism of action of Glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as Glimepiride. This is supported by both preclinical and clinical studies demonstrating that Glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin.

Selecting the starting dose of Glimepiride & Pioglitazone 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 Pioglitazone & Glimepiride be administered once daily with the first main meal.

Starting dose for patients currently on Glimepiride monotherapy: Based on the usual starting dose of Pioglitazone (15 mg or 30 mg daily), Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients currently on Pioglitazone monotherapy: Based on the usual starting doses of Glimepiride (1 mg or 2 mg once daily), and Pioglitazone 15 mg or 30 mg, Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg 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: Pioglitazone & Glimepiride may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of Pioglitazone and Glimepiride already being taken. Patients who are not controlled with 15 mg of Pioglitazone in combination with Glimepiride should be carefully monitored when switched to  Pioglitazone & Glimepiride.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of Pioglitazone plus a different sulfonylurea: No exact dosage relationship exists between Glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg Glimepiride, Pioglitazone & Glimepiride should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Glimepiride: 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. When these drugs are administered to a patient receiving Glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving Glimepiride, the patient should be observed closely for hypoglycemia. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. Potential interactions of Glimepiride with other drugs metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid.

Pioglitazone: Co-administration of Pioglitazone and an oral contraceptive resulted in decrease in ethinyl estradiol plasma concentrations. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In other drug-drug interaction studies, Pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.

Combination of Pioglitazone and Glimepiride is contraindicated in patients with:

• Known hypersensitivity to Pioglitazone or Glimepiride or any of the components of combination of Pioglitazone or Glimepiride.
• Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

Pioglitazone: The most common adverse experiences with Pioglitazone monotherapy (≥5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when Pioglitazone was used in combination with a sulfonylurea were similar to those during monotherapy with Pioglitazone. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and Pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively. In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with Pioglitazone versus 1.2% of placebo treated patients.

Glimepiride: Hypoglycemia: The incidence of hypoglycemia with Glimepiride is documented. In patients treated with Glimepiride, adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in more than 1% of patients included dizziness (1.7%), asthenia (1.6%), headache (1.5%), and nausea (1.1%). Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of Glimepiride.

Pregnancy category C. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Combination of Pioglitazone and Glimepiride should not be used during pregnancy.

Nursing mothers: No studies have been conducted with combination of Pioglitazone and Glimepiride. It is not known whether Pioglitazone and/or Glimepiride are excreted in human milk. Because many drugs are excreted in human milk, combination of Pioglitazone and Glimepiride should not be administered to a nursing woman.

General: Due to the mechanisms of action, Pioglitazone is active only in the presence of endogenous insulin. Therefore, combination of Pioglitazone and Glimepiride should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: 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 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.

Loss of Control of Blood Glucose: 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.

Edema: 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, combination of Pioglitazone and Glimepiride should be used with caution in patients at risk for heart failure.

Weight Gain: 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.

Hepatic Effects: 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 >2.5X upper limit of normal). If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with combination of Pioglitazone and Glimepiride, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >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.

Symptoms: Severe hypoglycaemia with coma, seizure, or neurological impairment.

Management: Admin glucagon or IV glucose. Additional carbohydrate intake may be necessary as hypoglycaemia may recur after apparent clinical recovery.

Combination Oral hypoglycemic preparations.

Pediatric Uses: Safety and effectiveness of combination of Pioglitazone and Glimepiride in pediatric patients have not been established.

Geriatric use:

• Pioglitazone: Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of Pioglitazone. Therefore, no dosage adjustments are required for the elderly.
• Glimepiride: The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Store in a cool and dry place. Protect from light and moisture. Keep out of the reach of the children.