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Hepatic Impairment: Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/ C) compared to healthy subjects. As a result, unbound Cmax and AUC0-inf were increased 2-and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects. Therapy with AVANDAMET should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal) at baseline (see PRECAUTIONS, Hepatic Effects). No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency. Text Continues Below
Geriatrics Results of the population pharmacokinetics analysis (n = 716 <65 years; n = 331 65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone. However, limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see GLUCOPHAGE prescribing information and CLINICAL PHARMACOLOGY, Pharmacokinetics). Metformin treatment and therefore treatment with AVANDAMET should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION). Gender: Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642). In rosiglitazone and metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response. 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 hydrochloride tablets was comparable in males and females. Race: Results of a population pharmacokinetic analysis including subjects of white, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone. No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics
(n = 24). Pediatrics No pharmacokinetic data from studies in pediatric subjects are available for either rosiglitazone or metformin. CLINICAL STUDIES There have been no clinical efficacy trials conducted with AVANDAMET tablets. However, studies utilizing the separate components have established the effective and safe use, and the additive benefit of the combination has been shown in patients with diabetes mellitus inadequately controlled with fasting plasma glucose between 140 and 300 mg/ dL despite maximal metformin therapy alone (2,500 mg/ day). Bioequivalence of AVANDAMET with coadministered rosiglitazone maleate tablets and metformin hydrochloride tablets was demonstrated (see CLINICAL PHARMACOLOGY, Pharmacokinetics). The addition of rosiglitazone to metformin resulted in significant improvements in glucose concentrations compared to either of these agents alone. These results are consistent with an additive effect on glycemic control when rosiglitazone is used in combination with metformin. No clinical trials have been conducted with combination rosiglitazone and metformin therapy as initial therapy in patients with type 2 diabetes mellitus. No controlled clinical trials have been conducted in which metformin was added to patients inadequately controlled with rosiglitazone alone. The pattern of LDL and HDL changes following therapy with rosiglitazone in combination with metformin was generally similar to those seen with rosiglitazone in monotherapy. Clinical Trials of Rosiglitazone Add-on Therapy in Patients Not Adequately Controlled on Metformin Alone: A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/ active-controlled studies designed to assess the efficacy of rosiglitazone in combination with metformin. Rosiglitazone maleate, administered in either once-daily or twice-daily dosing regimens, was added to the therapy of patients who were inadequately controlled on 2.5 grams/ day of metformin hydrochloride.
In one study, patients inadequately controlled on 2.5 grams/ day of metformin hydrochloride (mean baseline FPG 216 mg/ dL and mean baseline HbA1c 8.8%) were randomized to receive rosiglitazone 4 mg once daily, rosiglitazone 8 mg once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and rosiglitazone 4 mg once daily and rosiglitazone 8 mg once daily, versus patients continued on metformin alone (see Table 2). Table 2. Glycemic Parameters in a 26-Week Rosiglitazone maleate + Metformin
hydrochloride Combination Study
Metformin
Rosiglitazone 4 mg
once daily +metformin
Rosiglitazone 8 mg
once daily +metformin
N 113 116 110 FPG (mg/ dL)
Baseline (mean) 214 215 220 Change from baseline (mean) 6 -33 -48
Difference from metformin alone (adjusted mean) -40* -53*
Responders ( 30 mg/ dL decrease from baseline) 20% 45% 61%
HbA1c (%) Baseline (mean) 8.6 8.9 8.9
Change from baseline (mean) 0.5 -0.6 -0.8 Difference from metformin alone
(adjusted mean) -1.0* -1.2* Responders ( 0.7% decrease
from baseline) 11% 45% 52%
*p< 0.0001 compared to metformin. In a second 26-week study, patients with type 2 diabetes inadequately controlled on 2.5 grams/ day of metformin hydrochloride who were randomized to receive the combination of rosiglitazone 4 mg twice daily and metformin (N = 105) showed a statistically significant improvement in glycemic control with a mean treatment effect for FPG of -56 mg/ dL and a
mean treatment effect for HbA1c of -0.8% over metformin alone. The combination of metformin and rosiglitazone resulted in lower levels of FPG and HbA1c than either agent alone.
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