Cytochrome P450: See PRECAUTIONS, DRUG INTERACTIONS, Pioglitazone hydrochloride

In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine HCl or theophylline.

Metformin hydrochloride

See PRECAUTIONS, DRUG INTERACTIONS, Metformin hydrochloride

Pioglitazone hydrochloride

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin levels, and lower A1C values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least one year. In controlled clinical studies, pioglitazone in combination with metformin had an additive effect on glycemic control.

Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16-week and 24-week combination therapy studies of pioglitazone with metformin.

CLINICAL STUDIES

There have been no clinical efficacy studies conducted with ACTOPLUS MET. However, the efficacy and safety of the separate components have been previously established and the co-administration of the separate components has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in patients with inadequately controlled type 2 diabetes while on metformin therapy. Bioequivalence of ACTOPLUS MET with co-administered pioglitazone and metformin tablets was demonstrated for both ACTOPLUS MET strengths (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism).

Two treatment-randomized, controlled clinical studies in patients with type 2 diabetes were conducted to evaluate the safety and efficacy of pioglitazone plus metformin. Both studies included patients receiving metformin, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. All other antihyperglycemic agents were discontinued prior to starting study treatment. In the first study, 328 patients received either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their established metformin regimen. In the second study, 827 patients received either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their established metformin regimen.

In the first study, the addition of pioglitazone 30 mg once daily to metformin treatment significantly reduced the mean A1C by 0.83% and the mean FPG by 37.7 mg/dL at Week 16 from that observed with metformin alone. In the second study, the mean reductions from Baseline at Week 24 in A1C were 0.80% and 1.01% for the 30 mg and 45 mg doses, respectively. Mean reductions from Baseline in FPG were 38.2 mg/dL and 50.7 mg/dL, respectively. Based on these reductions in A1C and FPG (Table 2), the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose.

Table 2. Glycemic Parameters in 16-Week and 24-Week Pioglitazone Hydrochloride + Metformin Hydrochloride Combination Studies

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