Actoplus Met (Page 3 of 11)

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Ethnicity:

Pioglitazone hydrochloride

Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug-Drug Interactions

Co-administration of a single dose of metformin (1000 mg) and pioglitazone after 7 days of pioglitazone (45 mg) did not alter the pharmacokinetics of the single dose of metformin. Specific pharmacokinetic drug interaction studies with ACTOPLUS MET have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

Pioglitazone hydrochloride

The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed below:

Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Cmax . In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.

Nifedipine ER: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 — 0.95) for Cmax and 0.88 (0.80 — 0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

Ketoconazole: Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 — 1.23) for Cmax , 1.34 (1.26 — 1.41) for AUC and 1.87 (1.71 — 2.04) for Cmin .

Atorvastatin Calcium: Co-administration of pioglitazone for 7 days with atorvastatin calcium (LIPITOR®) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57 — 0.85) for Cmax , 0.76 (0.65 — 0.88) for AUC and 0.96 (0.87 — 1.05) for Cmin . For unchanged atorvastatin the ratio of least square mean (90% CI) values were 0.77 (0.66 — 0.90) for Cmax , 0.86 (0.78 — 0.94) for AUC and 0.92 (0.82 — 1.02) for Cmin .

Cytochrome P450: See PRECAUTIONS, Drug Interactions, Pioglitazone hydrochloride

Gemfibrozil: Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24 ) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see PRECAUTIONS, Drug Interactions, Pioglitazone hydrochloride).1

Rifampin: Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see PRECAUTIONS, Drug Interactions, Pioglitazone hydrochloride).2

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

Pharmacodynamics and Clinical Effects

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).

Clinical Trials of Pioglitazone Add-on Therapy in Patients Not Adequately Controlled on Metformin

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
Parameter Placebo + metformin Pioglitazone 30 mg + metformin
* significant change from Baseline p ≤ 0.050.
significant difference from placebo plus metformin, p ≤ 0.050.
‡ significant difference from 30 mg pioglitazone, p ≤ 0.050.
(a) patients who achieved an A1C ≤ 6.1% or ≥ 0.6% decrease from Baseline.
(b) patients who achieved a decrease in FPG by ≥ 30 mg/dL.
16-Week Study
A1C (%) N=153 N=161
Baseline mean 9.77 9.92
Mean change from Baseline at 16 Weeks 0.19 -0.64* , †
Difference in change from placebo + metformin -0.83
Responder rate (%) (a) 21.6 54.0
FPG (mg/dL) N=157 N=165
Baseline mean 259.9 254.4
Mean change from Baseline at 16 Weeks -5.2 -42.8* , †
Difference in change from placebo + metformin -37.7
Responder rate (%) (b) 23.6 59.4
Parameter Pioglitazone 30 mg + metformin Pioglitazone 45 mg + metformin
24-Week Study
A1C (%) N=400 N=398
Baseline mean 9.88 9.81
Mean Change from Baseline at 24 Weeks -0.80* -1.01*
Responder rate (%) (a) 55.8 63.3
FPG (mg/dL) N=398 N=399
Baseline mean 232.5 232.1
Mean Change from Baseline at 24 Weeks -38.2* -50.7* , ‡
Responder rate (%) (b) 52.3 63.7

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