Avandia - Clinical Pharmacology

with renal impairment, co-administration of metformin with AVANDIA is contraindicated in these patients.

Race

Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

Pediatric Use:

The safety and effectiveness of AVANDIA in pediatric patients have not been established.

CLINICAL STUDIES In clinical studies, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c), with a concurrent reduction in insulin and C-peptide. Postprandial glucose and insulin were also reduced. This is consistent with the mechanism of action of AVANDIA as an insulin sensitizer. The improvement in glycemic control was durable, with maintenance of effect for 52 weeks. The maximum recommended daily dose is 8 mg. Dose-ranging studies suggested that no additional benefit was obtained with a total daily dose of 12 mg.

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The addition of AVANDIA to either metformin, a sulfonylurea, or insulin resulted in significant reductions in hyperglycemia compared to any of these agents alone. These results are consistent with an additive effect on glycemic control when AVANDIA is used as combination therapy.

Patients with lipid abnormalities were not excluded from clinical trials of AVANDIA. In all 26-week controlled trials, across the recommended dose range, AVANDIA as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids.

These changes were statistically significantly different from placebo or glyburide controls (see Table 2).

Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/ HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week glyburide-controlled study is most pertinent to assess long-term effects on lipids. At baseline, week 26, and week 52, mean LDL/ HDL ratios were 3.1, 3.2, and 3.0, respectively, for AVANDIA 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between AVANDIA and glyburide at week 52 were statistically significant.