Gliclazide 60 mg, Metformin 500 mg, Pioglitazone 15 mg (SR) Tablets

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Absorption — The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride 500 to 1,500 mg and 850 to 2,550 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. At usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.

Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting.

Distribution — The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism — Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Elimination — Renal clearance (see Table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Renal Impairment — In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [See Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Hepatic Impairment — No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [See Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics — Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 3). [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Pediatrics — After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender — Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16).

Race — No studies of metformin pharmacokinetic parameters according to race have been performed.

In Vivo Assessment of Drug Interactions — Table 4: Effect of Co administered Drug on Plasma Metformin Systemic Exposure

‡ Ratio of arithmetic means — § At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Gliclazide is a sulfonylurea that increases insulin secretion from pancreatic beta cells. The cited product information also describes effects on platelet activity and vascular fibrinolysis.

For the cited immediate-release 80 mg tablets, plasma peaks occur about 2–6 hours after dosing. Protein binding is approximately 95%. Gliclazide is mainly metabolized in the liver; less than 1% of a dose is eliminated unchanged in urine. The reported elimination half-life is 10–12 hours. Modified-release presentations require their own absorption and exposure data.

Pioglitazone and metformin hydrochloride combines two antihyperglycemic agents: pioglitazone and metformin.

Pioglitazone — Pioglitazone is a thiazolidinedione that 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 not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Metformin hydrochloride — Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4) ] 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.

Pioglitazone and Metformin Hydrochloride — In bioequivalence studies of pioglitazone and metformin hydrochloride 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone hydrochloride 15 mg concomitantly administered with metformin hydrochloride immediate release (500 mg or 850 mg, respectively) tablets under fasted conditions in healthy subjects.

Administration of pioglitazone and metformin hydrochloride 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 — Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady state, in both healthy volunteers and patients with type 2 diabetes mellitus, pioglitazone comprises approximately 30 to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20 to 25% of the total AUC.

Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).

Metformin hydrochloride — The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2,550 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. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean Cmax, a 25% lower AUC, and a 35 minute prolongation of Tmax 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.

Pioglitazone — The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin.

Metformin hydrochloride — The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Pioglitazone — Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.