Pioglitazone & Metformin combination is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus. It is used in patients who are already receiving combined Pioglitazone and Metformin therapy, or in those whose diabetes is not adequately controlled with Metformin alone, or in patients who initially respond to Pioglitazone but require additional glycaemic control.

Pioglitazone requires the presence of insulin for its pharmacological action. It reduces insulin resistance in peripheral tissues and in the liver, leading to increased insulin-dependent glucose uptake and decreased hepatic glucose production. It is a potent and highly selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of this receptor regulates the transcription of insulin-responsive genes involved in glucose and lipid metabolism.

Metformin hydrochloride improves glucose tolerance in type 2 diabetes patients by lowering both fasting and postprandial blood glucose levels. It decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not cause hypoglycaemia in type 2 diabetes patients or healthy individuals and does not lead to hyperinsulinaemia.

General: The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of Pioglitazone 45 mg and Metformin 2550 mg.

Dosage Recommendations: Selecting the starting dose of Pioglitazone & Metformin should be based on the patient's current regimen of Pioglitazone and/or Metformin. Pioglitazone & Metformin should be given in divided daily doses with meals to reduce the gastrointestinal side effects associated with Metformin.

Starting dose for patients inadequately controlled on Metformin monotherapy Based on the usual starting dose of Pioglitazone (15-30 mg daily), Pioglitazone & Metformin may be initiated at either the 15 mg/500 mg or 15 mg/850 mg tablet strength once or twice daily, and gradually titrated after assessing adequacy of therapeutic response.

Starting dose for patients who initially responded to Pioglitazone monotherapy and require additional glycemic control Based on the usual starting doses of Metformin (500 mg twice daily or 850 mg daily), Pioglitazone & Metformin may be initiated at either the 15 mg/500 mg twice daily or 15 mg/850 mg tablet strength once daily, and gradually titrated after assessing adequacy of therapeutic response.

Starting dose for patients switching from combination therapy of Pioglitazone plus Metformin as separate tablets Pioglitazone & Metformin may be initiated with either the 15 mg/500 mg or 15 mg/850 mg tablet strengths based on the dose of Pioglitazone and Metformin already being taken.

Maximum Recommended Dose: Pioglitazone & Metformin tablets are available as a 15 mg Pioglitazone plus 500 mg Metformin or a 15 mg Pioglitazone plus 850 mg Metformin formulation for oral administration. The maximum recommended dose for Pioglitazone is 45 mg daily. The maximum recommended daily dose for Metformin is 2550 mg in adults.

Special Patient Populations: The initial and maintenance dosing of combination of Pioglitazone and Metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of combination of Pioglitazone and Metformin. Monitoring of renal function is necessary to aid in prevention of Metformin associated lactic acidosis, particularly in the elderly. Therapy with combination of Pioglitazone and Metformin should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy. Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with combination of Pioglitazone and Metformin and periodically thereafter.

Pioglitazone & Metformin combination may reduce vitamin B12 absorption. Plasma levels of Pioglitazone may increase when used with strong CYP2C8 inhibitors (e.g. gemfibrozil), and decrease with CYP2C8 inducers (e.g. rifampicin). Metformin exposure may be altered by cationic drugs eliminated via renal tubular secretion, leading to changes in drug clearance.

This combination is contraindicated in patients with

• renal disease or renal dysfunction (serum creatinine >1.5 mg/dl in males or >1.4 mg/dl in females, or abnormal creatinine clearance), including conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
• It is also contraindicated in patients with known hypersensitivity to Pioglitazone, Metformin, or any component of the formulation,
• and in acute or chronic metabolic acidosis including diabetic ketoacidosis with or without coma.

This combination is generally well tolerated. The most common adverse effects include upper respiratory tract infection, diarrhea, peripheral edema, and headache. These effects are usually mild in nature.

Pregnancy: There are no adequate and well-controlled studies in pregnant women for this combination or its individual components. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mother: It is not known whether Pioglitazone or Metformin is excreted in human milk. Since many drugs pass into breast milk, this combination should not be used during breastfeeding.

Pioglitazone works only in the presence of insulin and should not be used in type 1 diabetes or diabetic ketoacidosis. It should be used cautiously in combination therapy, especially with insulin, and in patients with hepatic impairment or heart disease.

Metformin is primarily eliminated by the kidney, and accumulation may lead to lactic acidosis, especially in renal impairment. Therefore, patients with elevated serum creatinine should not receive this combination. Renal function should be monitored regularly.

In elderly patients, dose selection should be cautious due to possible reduced renal function. Renal monitoring is important to prevent metformin-associated lactic acidosis. The combination should not be started in patients with active liver disease. Liver enzymes should be checked before initiation and periodically during therapy.

In case of overdose, appropriate supportive and symptomatic treatment should be provided based on the patient’s clinical condition.

Combination oral hypoglycaemic preparations

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