Metopa contains pioglitazone hydrochloride and metformin hydrochloride, two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes. Pioglitazone is a member of the thiazolidinedione class and metformin is a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Metopa is indicated for type 2 diabetic patients as an adjunct to diet and exercise to improve glycemic control.

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 hydrochloride 2550 mg. Selecting the starting dose of Metopa® should be based on the patient's current regimen of pioglitazone and/or metformin. Metopa® 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), Metopa® may be initiated at 15 mg/500 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 hydrochloride (500 mg twice daily), Metopa® may be initiated at the 15 mg/500 mg twice 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: Metopa® may be initiated with 15 mg/500 mg tablet strengths based on the dose of pioglitazone and metformin already being taken.

Maximum recommended dose: Metopa® tablets are available as a 15 mg pioglitazone plus 500 mg metformin hydrochloride 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.

Metformin and pioglitazone combination is contraindicated in patients with renal disease or renal dysfunction, or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia, known hypersensitivity to pioglitazone, metformin or any other component of metformin and pioglitazone combination and acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Upper-respiratory tract infections, diarrhoea, nausea, headache, urinary tract infection, sinusitis, dizziness, edema of lower limb, weight increase etc.

General: Pioglitazone hydrochloride: Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, combination of pioglitazone and metformin hydrochloride should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Metformin hydrochloride: Metformin is known to be substantially excreted by the kidney and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive combination of pioglitazone and metformin.
Hypoglycemia: Pioglitazone hydrochloride: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary. Metformin hydrochloride: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas or insulin) or ethanol.

Cardiovascular: Pioglitazone hydrochloride: Cases of congestive heart failure have been reported in patients both with and without previously known heart disease.
Edema: Combination of pioglitazone and metformin should be used with caution in patients with edema. Since thiazolidinedione, including pioglitazone can cause fluid retention, which can exacerbate or lead to congestive heart failure, combination of pioglitazone and metformin should be used with caution in patients at risk for heart failure.

Hepatic Effects: Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with combination of pioglitazone and metformin hydrochloride in all patients and periodically thereafter for the clinical judgment by the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. If jaundice is observed, drug therapy should be discontinued.

Loss of control of blood glucose: When a patient stabilized on any diabetic 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 metformin and temporarily administer insulin. Combination of pioglitazone and metformin may be reinstituted after the acute episode is resolved.

There is no well-controlled study of pioglitazone and metformin combination on pregnant and lactating human population. Study with rodents show that pioglitazone and metformin combination has no teratogenicity. Pregnancy category is C.

Pioglitazone hydrochloride:
In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP450 isoform 3A4 substrate.
Metformin hydrochloride:
i) Furosemide: A single-dose, metformin -furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.
ii) Nifedipine: Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
iii) Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Metformin had no effect on cimetidine pharmacokinetics.
iv) Others: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving combination of pioglitazone and metformin, the patient should be closely observed to maintain adequate glycemic control.
 

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

Metopa^® tablet : Box containing 3 strips of 10 tablets each. Each film coated tablet contains metformin hydrochloride BP 500 mg and pioglitazone hydrochloride INN equivalent to pioglitazone 15 mg. 



Manufactured by:
ESKAYEF BANGLADESH LTD
DHAKA, BANGLADESH
® REGD.TRADEMARK