Repaglinide

In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of repaglinide, may be altered by substances which influence these cytochrome P-450 enzymes via inhibition or induction. Special care should be taken when both inhibitors of CYP2C8 and 3A4 are co-administered simultaneously with repaglinide.

The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme (ACE)-inhibitors, salicylates, NSAIDs, octreotide, alcohol, and anabolic steroids.

Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin.

β-blocking medicinal products may mask the symptoms of hypoglycaemia.

The following substances may reduce the hypoglycaemic effect of repaglinide: oral contraceptives, barbiturates, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics.

When these medications are administered to or withdrawn from a patient receiving repaglinide, the patient should be observed closely for changes in glycaemic control.

Studies in animals have shown reproductive toxicity.

In a study conducted in healthy volunteers, the concomitant administration of repaglinide (a single dose of 0.25 mg) and ciclosporin (repeated dose at 100 mg) increased repaglinide AUC and C_max about 2.5-fold and 1.8-fold respectively. Since the interaction has not been established with dosages higher than 0.25 mg for repaglinide, the concomitant use of ciclosporin with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed.

In an interaction study in healthy volunteers, co-administration of 250 mg clarithromycin, a potent mechanism-based inhibitor of CYP3A4, slightly increased the repaglinide (AUC) by 1.4-fold and C_max by 1.7-fold and increased the mean incremental AUC of serum insulin by 1.5-fold and the maximum concentration by 1.6-fold. The exact mechanism of this interaction is not clear.

Co-administration of clopidogrel (300 mg loading dose), a CYP2C8 inhibitor, increased repaglinide exposure (AUC_0-∞) 5.1-fold and continued administration (75 mg daily dose) increased repaglinide exposure (AUC_0-∞) 3.9-fold. A small, significant decrease in blood glucose values was observed.

In an interaction study with healthy volunteers, co-administration of deferasirox (30 mg/kg/day, 4 days), a moderate inhibitor of CYP2C8 and CYP3A4, and repaglinide (single dose, 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold (90% CI [2.03-2.63]) of control, a 1.6-fold (90% CI [1.42-1.84]) increase in C_max, and a small, significant decrease in blood glucose values. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed.

Co-administration of 100 mg itraconazole, an inhibitor of CYP3A4, has also been studied in healthy volunteers, and increased the AUC by 1.4-fold. No significant effect on the glucose level in healthy volunteers was observed.

The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the pharmacokinetics of repaglinide has been studied in healthy subjects. Co-administration of 200 mg ketoconazole increased the repaglinide (AUC and C_max) by 1.2-fold with profiles of blood glucose concentrations altered by less than 8% when administered concomitantly (a single dose of 4 mg repaglinide).

Combination treatment with metformin is associated with an increased risk of hypoglycaemia.

Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of the metabolism of repaglinide. Seven days pre-treatment with rifampicin (600 mg), followed by co-administration of repaglinide (a single dose of 4 mg) at day seven resulted in a 50% lower AUC (effect of a combined induction and inhibition). When repaglinide was given 24 hours after the last rifampicin dose, an 80% reduction of the repaglinide AUC was observed (effect of induction alone).

Concomitant use of rifampicin and repaglinide might therefore induce a need for repaglinide dose adjustment which should be based on carefully monitored blood glucose concentrations at both initiation of rifampicin treatment (acute inhibition), following dosing (mixed inhibition and induction), withdrawal (induction alone) and up to approximately two weeks after withdrawal of rifampicin where the inductive effect of rifampicin is no longer present. It cannot be excluded that other inducers, e.g. phenytoin, carbamazepine, phenobarbital, St John’s wort, may have a similar effect.

Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, C_max and t_½ (1.6-fold, 1.4-fold and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety profile of this combination has not been established with dosages higher than 0.25 mg for repaglinide and 320 mg for trimethoprim, the concomitant use of trimethoprim with repaglinide should be avoided. If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.

The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction).

There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy.

There are no studies in breast-feeding women. Repaglinide should not be used in breast-feeding women.

Fertility

Studies in animals have shown reproductive toxicity.

Repaglinide has no direct influence on the ability to drive and use machines but may cause hypoglycaemia. Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.