tion therapy with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies.
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
When a patient stabilised on any oral hypoglycaemic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis.
The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction) (see sections 4.8 and 5.1).
Concomitant use
Repaglinide should be used with caution or be avoided in patients receiving drugs which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.
Specific patient groups
No clinical studies have been conducted in patients with impaired hepatic function. No clinical studies have been performed in children and adolescents < 18 years of age or in patients> 75 years of age. Therefore, treatment is not recommended in these patient groups.
Careful dose titration is recommended in debilitated or malnourished patients. The initial and maintenance dosages should be conservative (see section 4.2).
4.5 Interaction with other medicinal products and other forms of interaction
A number of drugs are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician:
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 drugs 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.
Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Drugs that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below).
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketokonazole, trimethoprim, ciclosporin, other antidiabetic agents, monoamine oxidase inhibitors (MAOI), non selective beta blocking agents, angiotensin converting enzyme (ACE)-inhibitors, salicylates, NSAIDs, octreotide, alcohol, and anabolic steroids.
Co-administration of gemfibrozil, (600 mg twice daily), an inhibitor of CYP2C8, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC 8.1-fold and Cmax 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7 hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use of gemfibrozil a |
