A dose-dependent decrease in blood glucose was demonstrated in type 2 diabetic patients when administered in doses from 0.5 to 4 mg repaglinide.

Clinical study results have shown that repaglinide is optimally dosed in relation to main meals (preprandial dosing).

Doses are usually taken within 15 minutes of the meal, but the time may vary from immediately preceding the meal to as long as 30 minutes before the meal.

One epidemiological study suggested an increased risk of acute coronary syndrome in repaglinide treated patients as compared to sulfonylurea treated patients (see sections 4.4 and 4.8).

5.2 Pharmacokinetic properties

 Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the drug. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidly, and repaglinide is eliminated within 4 - 6 hours. The plasma elimination half-life is approximately one hour.

Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%), low volume of distribution, 30 L (consistent with distribution into intracellular fluid), and rapid elimination from the blood.

A high interindividual variability (60%) in repaglinide plasma concentrations has been detected in the clinical trials. Intraindividual variability is low to moderate (35%) and as repaglinide should be titrated against the clinical response, efficacy is not affected by interindividual variability.

Repaglinide exposure is increased in patients with hepatic insufficiency and in the elderly type 2 diabetic patients. The AUC (SD) after 2 mg single dose exposure (4 mg in patients with hepatic insufficiency) was 31.4 ng/ml x hr (28.3) in healthy volunteers, 304.9 ng/ml x hr (228.0) in patients with hepatic insufficiency, and 117.9 ng/ml x hr (83.8) in the elderly type 2 diabetic patients.

After a 5 day treatment of repaglinide (2 mg x 3/day) in patients with a severe impaired renal function (creatinine clearance: 20-39 ml/min.), the results showed a significant 2-fold increase of the exposure (AUC) and half-life (t1/2) as compared to subjects with normal renal function.

Repaglinide is highly bound to plasma proteins in humans (greater than 98%).

No clinically relevant differences were seen in the pharmacokinetics of repaglinide, when repaglinide was administered 0, 15 or 30 minutes before a meal or in fasting state.

Repaglinide is almost completely metabolised, and no metabolites with clinically relevant hypoglycaemic effect have been identified.

Repaglinide and its metabolites are excreted primarily via the bile. A small fraction (less than 8%) of the administered dose appears in the urine, primarily as metabolites. Less than 1% of the parent drug is recovered in faeces.
5.3 Preclinical safety data

 Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients

 Microcrystalline cellulose (E460)

Calcium hydrogen phosphate, anhydrous

Maize starch

Amberlite (polacrilin potassium)

Povidone (polyvidone)

Glycerol 85%

Magnesium stearate

Meglumine

Po