Introduction
Metiglit tablet contains 2 oral antidiabetic drugs used in the management of Type 2 diabetes mellitus: Rosiglitazone maleate and Metformin hydrochloride. The combination of Rosiglitazone maleate and Metformin hydrochloride has been previously approved based on clinical trials in people with Type 2 diabetes mellitus inadequately controlled on Metformin alone.

Chemical Structure Chemically, Rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2, 4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecular formula is C18H19N3O3S¥C4H4O4.

Clinical Pharmacology
Mechanism of Action: Metiglit combines 2 antidiabetic agents with different mechanisms of action to improve glycemic control in patients with Type 2 diabetes. Rosiglitazone maleate, a member of the Thiazolidinedione class, and Metformin hydrochloride, 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. Rosiglitazone improves glycemic control by improving insulin sensitivity while reducing circulating insulin levels. Rosiglitazone is a highly selective and potent agonist for the Peroxisome Proliferator–Activated Receptor-Gamma (PPARg). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARg nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport and utilization. In addition, PPARg-responsive genes also participate in the regulation of fatty acid metabolism.
Metformin hydrochloride improves glucose tolerance in patients with Type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization. Unlike sulfonylureas, Metformin does not produce hypoglycemia in either patients with Type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With Metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day long plasma insulin response may actually decrease.

Pharmacokinetics
Absorption and Bioavailability: In a bioequivalence and dose proportionality study, both the Rosiglitazone component and the Metformin component were bioequivalent to coadministered 4 mg Rosiglitazone maleate tablet and 500 mg Metformin hydrochloride tablet under fasted conditions. In this study, dose proportionality of Rosiglitazone in the combination formulations of 1 mg/500 mg and 4 mg/500 mg was demonstrated.

Indication
This combination is indicated as an adjunct to diet and exercise to improve glycemic control in patients with Type-2 diabetes mellitus who are not adequately controlled on Rosiglitazone or Metformin alone.

Dosage and Administration

Cautions
In patients with advanced age, this combination should be carefully titrated to establish the minimum dose for adequate glycemic effects, because aging is associated with reduced renal function.
Use in Renal Impairment: Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metiglit should only be used in patients with normal renal function
Use in Elderly Patient: Generally, elderly patients should not be titrated to the maximum dose of Metiglit
Use in Pregnancy & Lactaion: This combination should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Administration to nursing mother is not recommended.
Use in Children: Safety and effectiveness of Metiglit in pediatric patients have not been reported.

Side effects
Upper respiratory tract infections, Diarrhea, Headache, Anemia, Oedema, Hypoglycemia, Less commonly fatigue, Back pain, Arthralgia & rarely hyperglycemia.

Contraindication
Renal disease or renal dysfunction, Congestive heart failure, Known hypersensitivity to Rosiglitazone or Metformin, Acute or chronic metabolic acidosis, including diabetic ketoacidosis etc.

Drug Interactions
Drugs metabolized by cytochrome P-450 isoenzyme, frusemide, nifedipine, cationic drugs, diuretics, corticosteroids, phenothiazines, oral contraceptives, etc.

Over dosage
Rosiglitazone maleate: Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, Rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patientÕs clinical status.
Metformin hydrochloride: Hypoglycemia has not been seen with ingestion of up to 85 grams of Metformin hydrochloride, although lactic acidosis has occurred in such circumstances Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated Metformin from patients in whom Metformin overdosage is suspected.

How Supplied
Metiglit 1: Each box contains 3 blister packs of 10 tablets.
Metiglit 2: Each box contains 3 blister packs of 10 tablets.