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Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg adminis-tered twice daily resulted in least square mean (90% Cl) 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 ACTOS for 7 days with atorvastatin calcium (LIPITOR ® ) 80 mg once daily resulted in least square mean (90% Cl) 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 least square mean (90% Cl) 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. Theophylline:
Co-administration of ACTOS for 7 days with theophylline 400 mg adminis-tered twice daily resulted in no change in the pharmacokinetics of either drug. Oral Contraceptives: See PRECAUTIONS. Cytochrome P450: See PRECAUTIONS. Text Continues Below
Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS 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 pro-CH3 duced by ACTOS results in lower blood glucose concentrations, lower plasma insulin levels, and lower HbA1c values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical trials, ACTOS in combination with sulfonylurea, metformin, or insulin had an addi-tive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean increase in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placebo-Controlled Dose-Ranging Study
ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg
Once Daily Once Daily Once Daily
Triglycerides (mg/ dL) N= 79 N= 79 N= 84 N= 77 Baseline (mean) 262.8% 283.8% 261.1% 259.7% Percent change from 4.8% -9.0% -9.6% -9.3% baseline (mean)
HDL Cholesterol (mg/ dL) N= 79 N= 79 N= 83 N= 77 Baseline (mean) 41.7% 40.4% 40.8% 40.7%
Percent change from 8.1% 14.1% 12.2% 19.1% baseline (mean)
LDL Cholesterol (mg/ dL) N= 65 N= 63 N= 74 N= 62 Baseline (mean) 138.8% 131.9% 135.6% 126.8%
Percent change from 4.8% 7.2% 5.2% 6.0% baseline (mean)
Total Cholesterol (mg/ dL) N= 79 N= 79 N= 84 N= 77 Baseline (mean) 224.6% 220.0% 222.7% 213.7%
Percent change from 4.4% 4.6% 3.3% 6.4% baseline (mean) In the two other monotherapy studies (24 weeks and 16 weeks) and in combination therapy studies with sulfonylurea (16 weeks) and metformin (16 weeks), the results were generally consistent with the data above. For patients treated with ACTOS, the corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL cholesterol. In the combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. Clinical Studies Monotherapy In the U. S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting blood glucose (FBG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FBG and HbA1c for the entire study population in this 26-week study. Figure 1 Mean Change from Baseline for FBG and HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study Table 2 shows HbA1c and FBG values for the entire study population.
Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study
ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Daily Once Daily Once Daily
Total Population
HbA1c (%) N= 79 N= 79 N= 85 N= 76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline 0.7 -0.3 -0.3 -0.9 (adjusted mean + )
Difference from placebo -1.0* -1.0* -1.6* (adjusted mean + ) FBG (mg/ dL) N= 79 N= 79 N= 84 N= 77 Baseline (mean) 268 267 269 276
Change from baseline 9 -30 -32 -56 (adjusted mean + )
Difference from placebo -39* -41* -65* (adjusted mean + ) + Adjusted for baseline, pooled center, and pooled center by treatment interaction
*p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/ run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FBG values from screening to baseline for the naïve patients; however, for the previously-mellitus treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FBG. Although most patients in the previously-muscle treated group had a decrease from baseline in HbA1c and FBG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study
ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Daily Once Daily Once Daily
Naïve to Therapy
HbA1c (%) N= 25 N= 26 N= 26 N= 21
Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline 0.6 -0.8 -0.6 -1.9 (adjusted mean*)
Difference from placebo -1.4 -1.3 -2.6 (adjusted mean*) FBG (mg/ dL) N= 25 N= 26 N= 26 N= 21
Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline 216 -37 -41 -64 (adjusted mean*)
Difference from placebo -52 -56 -80 (adjusted mean*) Previously Treated
HbA1c (%) N= 54 N= 53 N= 59 N= 55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline 0.8 -0.1 -0.0 -0.6 (adjusted mean*)
Difference from placebo -1.0 -0.9 -1.4 (adjusted mean*) FBG (mg/ dL) N= 54 N= 53 N= 58 N= 56
Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline 224 -32 -27 -55 (adjusted mean*)
Difference from placebo -36 -31 -59 (adjusted mean*) * Adjusted for baseline and pooled center In a 24-week study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. In one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After placebo-four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FBG at endpoint compared to placebo (see Table 4). Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study
ACTOS ACTOS Placebo + 30 mg + + 45 mg + Once Daily Once Daily Total Population HbA1c (%) N= 83 N= 85 N= 85 Baseline (mean) 10.8 10.3 10.8
Change from baseline 0.9 -0.6 -0.6 (adjusted mean ++ )
Difference from placebo -1.5* -1.5* (adjusted mean ++ ) FBG (mg/ dL) N= 78 N= 82 N= 85
Baseline (mean) 279 268 281 Change from baseline 218 -44 -50 (adjusted mean ++ ) Difference from placebo -62* -68*
(adjusted mean ++ ) +
Final dose in forced titration ++ Adjusted for baseline, pooled center, and pooled center by treatment interaction *p 0.050 vs. placebo
For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA1c and 238 mg/ dL for FBG. At baseline, mean HbA1c was 10.2% and mean FBG was 243 mg/ dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 2.3% and 2.6% and mean FBG of 63 mg/ dL and 95 mg/ dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medi-cation was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/ dL for FBG. At baseline, mean HbA1c was 10.7% and mean FBG was 290 mg/ dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 1.3% and 1.4% and mean FBG of 55 mg/ dL and 60 mg/ dL, respectively. For many previously-treated patients, HbA1c and FBG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1c and FBG at endpoint compared to placebo (see Table 5).
Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study ACTOS 30 mg Placebo Once Daily Total Population
HbA1c (%) N= 93 N= 100 Baseline (mean) 10.3 10.5
Change from baseline (adjusted mean + ) 0.8 -0.6 Difference from placebo (adjusted mean + ) -1.4*
FBG (mg/ dL) N= 91 N= 99
Baseline (mean) 270. 3 273 Change from baseline (adjusted mean + ) 278. 3 -50 Difference from placebo (adjusted mean + ) -58* +
Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1c and 240 mg/ dL for FBG. At baseline, mean HbA1c was 10.4% and mean FBG was 254 mg/ dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.0% and mean FBG of 62 mg/ dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/ dL for FBG. At baseline, mean HbA1c was 10.6% and mean FBG was 287 mg/ dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline
in mean HbA1c of 1.3% and mean FBG of 46 mg/ dL. For many previously-treated patients, HbA1c and FBG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies were con-for ducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. In one combination study, 560 patients with type 2 diabetes on a sulfonylurea, either alone or combined with another antidiabetic agent, were randomized to receive 15 mg or 30 mg of ACTOS or placebo once daily in addition to their current sulfonylurea regimen. Any other antidiabetic agent was withdrawn. Compared with placebo, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3% for the 15 mg and 30 mg doses, respectively. Compared with placebo, mean FBG decreased by 39 mg/ dL (15 mg dose) and 58 mg/ dL (30 mg dose). The therapeutic effect of ACTOS in combina-Nifedipine tion with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea (< 50%, 50%, or > 50% of the recommended maximum daily dose). In a second combination study, 328 patients with type 2 diabetes on metformin, either alone or combined with another antidiabetic agent, were randomized to receive either 30 mg of ACTOS or placebo once daily in addition to their metformin. Any other anti-diabetic agent was withdrawn. Compared to placebo, the addition of ACTOS to metformin significantly reduced the mean HbA1c by 0.8% and decreased the mean FBG by 38 mg/ dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin (< 2000 mg per day or 2000 mg per day). In a third combination study, 566 patients with type 2 diabetes receiving a median of 60.5 units per day of insulin, either alone or combined with another antidiabetic agent, were ran-domized to receive either 15 mg or 30 mg of ACTOS or placebo once daily in addition to their insulin. Any other antidiabetic agent was discontinued. Compared to placebo, treat-ment with ACTOS in addition to insulin significantly reduced both HbA1c (0.7% for the 15 mg dose and 1.0% for the 30 mg dose) and FBG (35 mg/ dL for the 15 mg dose and 49 mg/ dL for the 30 mg dose). The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin (< 60.5 units per day or 60.5 units per day). Page: << Prev | 1 | 2 | 3 | 4 | 5
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