etidine, nifedipine, oestrogen, or simvastatin with repaglinide, all CYP3A4 substrates, did not significantly alter the pharmacokinetic parameters of repaglinide.
Repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin at steady state, when administered to healthy volunteers. Dosage adjustment of these compounds when co-administered with repaglinide is therefore not necessary.
The following substances may reduce the hypoglycaemic effect of repaglinide:
Oral contraceptives, rifampicin, 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When these medications are administered to or withdrawn from a patient receiving repaglinide, the patient should be observed closely for changes in glycaemic control.
When repaglinide is used together with other drugs that are mainly secreted by the bile, like repaglinide, any potential interaction should be considered.
4.6 Pregnancy and lactation
There are no studies of repaglinide in pregnant or lactating women. Therefore the safety of repaglinide in pregnant women cannot be assessed. Up to now repaglinide showed not to be teratogenic in animal studies. Embryotoxicity, abnormal limb development in foetuses and new born pups, was observed in rats exposed to high doses in the last stage of pregnancy and during the lactation period. Repaglinide is detected in the milk of experimental animals. For that reason repaglinide should be avoided during pregnancy and should not be used in lactating women.
4.7 Effects on ability to drive and use machines
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness o the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 Undesirable effects
Based on the experience with repaglinide and with other hypoglycaemic agents the following adverse events have been seen: Frequencies are defined as: Common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
Immune system disorders
Very rare: Allergy
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.
Metabolism and nutrition disorders
Common: Hypoglycaemia
Not known: Hypoglycaemic coma and hypoglycaemic unconsciousness
As with other hypoglycaemic agents, hypoglycaemic reactions have been observed after administration of repaglinide. These reactions are mostly mild and easily handled through intake of carbohydrates. If severe, requiring third party assistance, infusion of glucose may be necessary. The occurrence of such reactions depends, as for every diabetes therapy, on individual factors, such as dietary habits, dosage, exercise and stress (see section 4.4). Interactions with other medicinal products may increase the risk of hypoglycaemia (see section 4.5). During post marketing experience, cases of hypoglycaemia have been reported in patients treated with repaglinide in combination with metformin or thiazolidinedione.
Gastro-intestinal disorders
Common: Abdominal pain and diarrhoea
Very rare: Vomiting and constipa
