SIDE EFFECTS

In worldwide clinical trials, over 3,700 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 2,500 patients have received ACTOS, over 1,100 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 6.

Table 6

Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency ³5% of ACTOS-Treated Patients

The types of clinical adverse events reported when ACTOS was used in combination with sulfonylureas (N=373), metformin (N=168), or insulin (N=379) were generally similar to those reported during ACTOS monotherapy with the exception of an increase in the occurrence of edema in the insulin combination study (pioglitazone 15% and placebo 7%). The incidence of withdrawals from clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%).

Mild to moderate hypoglycemia was reported during combination therapy with sulfonylurea or insulin. Hypoglycemia was reported for 1% of placebo-treated patients and 2% of patients when ACTOS was used in combination with a sulfonylurea. In combination with insulin, hypoglycemia was reported for 5% of placebo-treated patients, 8% for patients treated with 15 mg of ACTOS, and 15% for patients treated with 30 mg of ACTOS (see PRECAUTIONS, General, Hypoglycemia).

In U.S. double-blind studies, anemia was reported for 1.0% of ACTOS-treated patients and 0.0% of placebo-treated patients in monotherapy studies. Anemia was reported for 1.6% of ACTOS-treated patients and 1.6% of placebo-treated patients in combination with insulin. Anemia was reported for 0.3% of ACTOS-treated patients and 1.6% of placebo-treated patients in combination with sulfonylurea. Anemia was reported for 1.2% of ACTOS-treated patients and 0.0% of placebo-treated patients in combination with metformin.

In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema).

In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects).

Laboratory

Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in ACTOS-treated patients. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have not been associated with any significant hematologic clinical effects.

Serum Transaminase Levels: During placebo-controlled clinical trials in the U.S., a total of 4 of 1,526 (0.26%) ACTOS-treated patients and 2 of 793 (0.25%) placebo-treated patients had ALT values ³ 3 times the upper limit of normal. During all clinical studies in the U.S., 11 of 2,561 (0.43%) ACTOS-treated patients had ALT values ³ 3 times the upper limit of normal. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.12% of ACTOS-treated patients were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, General, Hepatic Effects).

CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. A single, isolated elevation to greater than 10 times the upper limit of normal (values of 2,150 to 8,610) was noted in 7 patients. Five of these patients continued to receive ACTOS and the other two patients had completed receiving study medication at the time of the elevated value. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown.

DRUG INTERACTIONS

Oral Contraceptives: Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. The pharmacokinetics of coadministration of ACTOS and oral contraceptives have not been evaluated in patients receiving ACTOS and an oral contraceptive. Therefore, additional caution regarding contraception should be exercised in patients receiving ACTOS and an oral contraceptive.

Glipizide: In healthy volunteers, coadministration of ACTOS (45 mg once daily) and glipizide (5.0 mg once daily) for seven days did not alter the steady-state pharmacokinetics of glipizide.

Digoxin: In healthy volunteers, coadministration of ACTOS (45 mg once daily) with digoxin (0.25 mg once daily) for seven days did not alter the steady-state pharmacokinetics of digoxin.

Warfarin: In healthy volunteers, coadministration of ACTOS (45 mg once daily) for seven days with warfarin did not alter the steady-state pharmacokinetics of warfarin. In addition, ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.

Metformin: In healthy volunteers, coadministration of metformin (1,000 mg) and ACTOS (45 mg) after seven days of ACTOS (45 mg once daily) did not alter the pharmacokinetics of the single dose of metformin.

The cytochrome P450 isoform C.P.A. is partially responsible for the metabolism of pioglitazone. Specific formal pharmacokinetic interaction studies have not been conducted with ACTOS and other drugs metabolized by this enzyme such as: erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, triazolam, and trimetrexate, as well as inhibitory drugs such as ketoconazole and itraconazole. In vitro, ketoconazole appears to significantly inhibit the metabolism of pioglitazone (see CLINICAL PHARMACOLOGY, Metabolism). Pending the availability of additional data, patients receiving ketoconazole concomitantly with ACTOS should be evaluated more frequently with respect to glycemic control.