Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Special Populations

Renal Insufficiency: The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects).

Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Pediatrics: Pharmacokinetic data in the pediatric population are not available.

Gender: The mean Cmax and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS improved glycemic control in both males and females. In controlled clinical trials, hemoglobin A_1c (HbA_1c) decreases from baseline were generally greater for females than for males (average mean difference in HbA_1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Ethnicity: Pharmacokinetic data among various ethnic groups are not available.

Drug-Drug Interactions

The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results:

Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

Fexofenadine HCl: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally twice daily resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics.

Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide.

Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin.

Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.

Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin.

Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.

Ranitidine HCl: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics.

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