Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd, Whiddon Valley, Barnstaple, Devon, EX32 8NS
Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction.
Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia.
The blood glucose-lowering effect of oral hypoglycaemic medicinal products decreases in many patients over time. This may be due to progression of the severity of the diabetes or to diminished responsiveness to the medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary failure, where the medicinal product is ineffective in an individual patient when first given. Adjustment of dose and adherence to diet and exercise should be assessed before classifying a patient as a secondary failure.
Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in case of secondary failure to insulin secretagogues has not been investigated in clinical trials. Trials investigating the combination with other insulin secretagogues have not been performed.
Trials of combination therapy with 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 medicinal product 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.
Repaglinide should be used with caution or be avoided in patients receiving medicinal products 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.
A number of medicinal products 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 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.
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 (see below).
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide:
Gemfibrozil, clarithromycin, itraconazole, ketokonazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, 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 and repaglinide is contraindicated (see section 4.3).
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, Cmax and t½ (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 (see section 4.4).
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.
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 Cmax) 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). 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. 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 Cmax 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.
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 Cmax 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 (see section 4.4).
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 Cmax, 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 (see section 4.4).
Co-administration of clopidogrel (300 mg loading dose), a CYP2C8 inhibitor, increased repaglinide exposure (AUC0-∞) 5.1-fold and continued administration (75 mg daily dose) increased repaglinide exposure (AUC0-∞) 3.9-fold. A small, significant decrease in blood glucose values was observed.
β-blocking medicinal products may mask the symptoms of hypoglycaemia.
Co-administration of cimetidine, 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 medicinal products that are mainly secreted by the bile, like repaglinide, any potential interaction should be considered.
No interaction studies have been performed in children and adolescents.
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.
Studies in animals have shown reproductive toxicity (see section 5.3).
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.
The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress.
Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions 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) and not known (cannot be estimated from the available data).
Very rare: Allergic reactions*
Common: Hypoglycaemia
Not known: Hypoglycaemic coma and hypoglycaemic unconsciousness
Very rare: Refraction disorder*
Rare: Cardiovascular disease
Common: Abdominal pain, diarrhoea
Very rare: Vomiting, constipation
Not known: Nausea
Very rare: Abnormal hepatic function, increased liver enzymes*
Not known: Hypersensitivity*
* see section Description of selected adverse reaction below
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.
Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials.
Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increased liver enzymes. In very rare cases, severe hepatic dysfunction has been reported.
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no reason to suspect cross-allergenicity with sulphonylurea due to the difference in chemical structure.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard.
Not applicable.
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