Actos - Warnings & Precautions

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Combination Sulfonylurea -0.5 (-1.8/ 0.7) 2.0 (0.2/ 3.2) 2.7 (1.1/ 4.5) N/ A Therapy n= 187 n= 183 n= 186

Metformin -1.4 (-3.2/ 0.3) N/ A 1.4 (-0.9/ 3.0) N/ A n= 160 n= 167

Insulin 0.2 (-1.4/ 1.4) 2.3 (0.5/ 4.3) 3.6 (1.4/ 5.9) N/ A n= 182 n= 190 n= 188

Ovulation:

Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in pre-menopausal women should be recommended. This possible effect has not been investi-gated in clinical studies so the frequency of this occurrence is not known.

Hematologic:

ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS.

These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have not been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities).

Hepatic Effects:

Another drug of the thiazolidinedione class, troglitazone, has been associ-ated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death have been reported during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associat-ed with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and very rare cases of reversible jaundice were reported. In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS.

In U. S. clinical studies, over 2500 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U. S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.