Glitos Plus™

[Pioglitazone + Metformin]

Description / Properties

Glitos Plus™ tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: Pioglitazone hydrochloride and Metformin hydrochloride. Mechanism of Action: Glitos Plus™ contains two antihyperglycemic drugs with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Pioglitazone hydrochloride, a member of the thiazolidinedione class, depends on the presence of insulin for its mechanism of action. It decreases insulin resistance in the periphery and in the liver resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, Pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.

Indications

Glitos Plus™ is indicated 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 metformin or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

Side Effects

Metformin HCl
Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Glitos Plus™ tablets; when it occurs, it is fatal in approximately 50% of cases. While reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient expose to Metformin in clinical trials, there were no reports of lactic acidosis.

Pioglitazone HCl
Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antihyperglycemic 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.

Warning and Precautions

With Metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics and Drug Metabolism: Administration of Glitos Plus™ 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant. Pioglitazone hydrochloride, Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Metformin hydrochloride, The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% - 60%.

Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration, a 25% lower AUC in plasma concentration versus time curve, and a 35 minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

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 while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and metformin 2550 mg.

Dosage Recommendations: Selecting the starting dose of Glitos Plus™ should be based on the patient's current regimen of pioglitazone and/or metformin. After initiation of Glitos Plus™ or with dose increase, patients should be carefully monitored for adverse events related to fluid retention. Glitos Plus™ 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), Glitos Plus™ 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), Glitos Plus™ 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. Glitos Plus™ 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.

Presentations Available

Glitos Plus™ 15/500 and 15/850 are available in packs of 14 tablets.

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