Levonorgestrel & Ethinyl Estradiol: Co-administration of a combination tablet of 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol administered once daily for 21 days with 2 mg PRANDIN administered three times daily (days 1-4) and a single dose on Day 5 resulted in 20% increases in repaglinide, levonorgestrel, and ethinyl estradiol C_max. The increase in repaglinide C_max was from 40.5 ng/mL to 47.4 ng/mL. Ethinyl estradiol AUC parameters were increased by 20%, while repaglinide and levonorgestrel AUC values remained unchanged.

Simvastatin: Co-administration of 20 mg simvastatin and a single dose of 2 mg PRANDIN (after 4 days of once daily simvastatin 20 mg and three times daily PRANDIN 2 mg) resulted in a 26% increase in repaglinide C_max from 23.6 ng/mL to 29.7 ng/mL. AUC was unchanged.

Nifedipine: Co-administration of 10 mg nifedipine with a single dose of 2 mg PRANDIN (after 4 days of three times daily nifedipine 10 mg and three times daily PRANDIN 2 mg) resulted in unchanged AUC and C_max values for both drugs.

Clarithromycin: Co-administration of 250 mg clarithromycin and a single dose of 0.25 mg PRANDIN (after 4 days of twice daily clarithromycin 250 mg) resulted in a 40% and 67% increase in repaglinide AUC and C_max, respectively. The increase in AUC was from 5.3 ng/mL*hr to 7.5 ng/mL*hr and the increase in C_max was from 4.4 ng/mL to 7.3 ng/mL.

Trimethoprim: Co-administration of 160 mg trimethoprim and a single dose of 0.25 mg PRANDIN (after 2 days of twice daily and one dose on the third day of trimethoprim 160 mg) resulted in a 61% and 41% increase in repaglinide AUC and C_max, respectively. The increase in AUC was from 5.9 ng/mL*hr to 9.6 ng/mL*hr and the increase in C_max was from 4.7 ng/mL to 6.6 ng/mL.

Renal Insufficiency. Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 - 80 mL/min), and severe renal function impairment (CrCl = 20 - 40 mL/min). Both AUC and C_max of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and C_max values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Initial dose adjustment does not appear to be necessary for patients with mild to moderate renal dysfunction. However, patients with type 2 diabetes who have severe renal function impairment should initiate PRANDIN therapy with the 0.5 mg dose subsequently, patients should be carefully titrated. Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.

Hepatic Insufficiency. A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUC_healthy: 91.6 ng/mL*hr; AUC_{CLD patients}: 368.9 ng/mL*hr; C_{max, healthy}: 46.7 ng/mL; C_{max, CLD patients}: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Patients with impaired liver function may be exposed to higher concentrations of repaglinide and its associated metabolites than would patients with normal liver function receiving usual doses. Therefore, PRANDIN should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments should be utilized to allow full assessment of response.

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