- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Dosimetry
- 12 Instructions for preparation of radiopharmaceuticals
PosologyRepaglinide is given preprandially and is titrated individually to optimise glycaemic control. In addition to the usual self-monitoring by the patient of blood and/or urinary glucose, the patient's blood glucose must be monitored periodically by the physician to determine the minimum effective dose for the patient. Glycosylated haemoglobin levels are also of value in monitoring the patient's response to therapy. Periodic monitoring is necessary to detect inadequate lowering of blood glucose at the recommended maximum dose level (i.e. primary failure) and to detect loss of adequate blood glucose lowering response after an initial period of effectiveness (i.e. secondary failure).Short-term administration of repaglinide may be sufficient during periods of transient loss of control in type 2 diabetic patients usually controlled well on diet.
Initial doseThe dosage should be determined by the physician, according to the patient's requirements.The recommended starting dose is 0.5 mg. One to two weeks should elapse between titration steps (as determined by blood glucose response).If patients are transferred from another oral hypoglycaemic medicinal product the recommended starting dose is 1 mg.
MaintenanceThe recommended maximum single dose is 4 mg taken with main meals.The total maximum daily dose should not exceed 16 mg.
ElderlyNo clinical studies have been conducted in patients >75 years of age.
Renal impairmentRepaglinide is primarily excreted via the bile and excretion is therefore not affected by renal disorders.Eight percent of one dose of repaglinide is excreted through the kidneys and total plasma clearance of the product is decreased in patients with renal impairment. As insulin sensitivity is increased in diabetic patients with renal impairment, caution is advised when titrating these patients.
Hepatic impairmentNo clinical studies have been conducted in patients with hepatic insufficiency
Debilitated or malnourished patientsIn debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful dose titration is required to avoid hypoglycaemic reactions.
Patients receiving other oral hypoglycaemic medicinal products)Patients can be transferred directly from other oral hypoglycaemic medicinal products to repaglinide. However, no exact dosage relationship exists between repaglinide and the other oral hypoglycaemic medicinal products. The recommended maximum starting dose of patients transferred to repaglinide is 1 mg given before main meals.Repaglinide can be given in combination with metformin, when the blood glucose is insufficiently controlled with metformin alone. In this case, the dosage of metformin should be maintained and repaglinide administered concomitantly. The starting dose of repaglinide is 0.5 mg, taken before main meals; titration is according to blood glucose response as for monotherapy.Paediatric population The safety and efficacy of repaglinide in children below 18 years have not been established. No data are available.
Method of administrationRepaglinide should be taken before main meals (i.e. preprandially). Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal (i.e. preprandially 2, 3, or 4 meals a day). Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal. In the case of concomitant use with other active substances refer to sections 4.4 and 4.5 to assess the dosage.
GeneralRepaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction.
HypoglycaemiaRepaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia.
Combination with insulin secretagoguesThe 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 products 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.
Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinedionesTrials 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 with metforminCombination 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.
Acute coronary syndromeThe 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 useRepaglinide 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.
PregnancyThere are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy.
Breast-feedingThere are no studies in breast-feeding women. Repaglinide should not be used in breast-feeding women.
FertilityStudies in animals have shown reproductive toxicity (see section 5.3).
Summary of the safety profileThe 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.
Tabulated list of adverse reactionsBased 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).
|Immune system disorders|
|Very rare:||Allergic reactions*|
|Metabolism and nutrition disorders|
|Not known:||Hypoglycaemic coma and hypoglycaemic unconsciousness|
|Very rare:||Refraction disorder*|
|Common:||Abdominal pain, diarrhoea|
|Very rare:||Vomiting, constipation|
|Very rare:||Abnormal hepatic function, increased liver enzymes*|
|Skin and subcutaneous tissue disorders|
Allergic reactionsGeneralised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.
Refraction disordersChanges 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.
Abnormal hepatic function, increased liver enzymesIsolated 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.
HypersensitivityHypersensitivity 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.
Mechanism of actionRepaglinide is a short-acting oral secretagogue. Repaglinide lowers the blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning β-cells in the pancreatic islets.Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a target protein different from other secretagogues. This depolarises the β-cell and leads to an opening of the calcium channels. The resulting increased calcium influx induces insulin secretion from the β-cell.
Pharmacodynamic effectsIn type 2 diabetic patients, the insulinotropic response to a meal occurred within 30 minutes after an oral dose of repaglinide. This resulted in a blood glucose-lowering effect throughout the meal period. The elevated insulin levels did not persist beyond the time of the meal challenge. Plasma repaglinide levels decreased rapidly, and low concentrations were seen in the plasma of type 2 diabetic patients 4 hours post-administration.
Clinical efficacy and safetyA 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).
AbsorptionRepaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the active substance. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidlyRepaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%). 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.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.
DistributionRepaglinide pharmacokinetics are characterised by low volume of distribution, 30 L (consistent with distribution into intracellular fluid) andis highly bound to plasma proteins in humans (greater than 98%).
EliminationRepaglinide is eliminated rapidly within 4 - 6 hours from the blood. The plasma elimination half-life is approximately one hour. Repaglinide is almost completely metabolised, and no metabolites with clinically relevant hypoglycaemic effect have been identified.Repaglinide 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 repaglinide is recovered in faeces.
Special patient groupsRepaglinide 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. Paediatric population No data are available.
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