Drug Class Description
Carbamoylmethyl benzoic acid derivative

Generic Name
Repaglinide

Drug Description
Repaglinide 0.5 mg or Repaglinide 1 mg or Repaglinide 2 mg respectively.

Presentation
TabletRepaglinide tablets are white (0.5 mg), yellow (1 mg), or peach-coloured (2 mg), round and convex and engraved with Novo Nordisk logo (Apis bull).

Indications
Repaglinide is indicated in patients with type 2 diabetes (Non Insulin-Dependent Diabetes Mellitus (NIDDM)) whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in type 2 diabetes patients who are not satisfactorily controlled on metformin alone. Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.

Adult Dosage
Repaglinide 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.Repaglinide 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.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 agent 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.Specific patient groupsRepaglinide 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.No clinical studies have been conducted in patients > 75 years of age or in patients with hepatic insufficiency.Repaglinide is not recommended for use in children below age 18 due to a lack of data on safety and/or efficacy.In 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 agents (OHAs)Patients can be transferred directly from other oral hypoglycaemic agents to repaglinide. However, no exact dosage relationship exists between repaglinide and the other oral hypoglycaemic agents. 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.

Child Dosage
No clinical studies have been performed in children and adolescents <18 years of age

Elderly Dosage
No clinical studies have been conducted in patients>75 years of age or in patients with hepatic insufficiency. Please see Special Precautions.

Contra Indications
• Hypersensitivity to repaglinide or to any of the excipients in Prandin• Type 1 diabetes (Insulin-Dependent Diabetes Mellitus: IDDM), C-peptide negative• Diabetic ketoacidosis, with or without coma• Severe hepatic function disorder• Concomitant use of gemfibrozil.

Special Precautions
GeneralRepaglinide 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 agents decreases in many patients over time. This may be due to progression of the severity of the diabetes or to diminished responsiveness to the product. This phenomenon is known as secondary failure, to distinguish it from primary failure, where the drug 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 and acarbose have not been performed.Trials of combination 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).Concomitant useRepaglinide should be used with caution or be avoided in patients receiving drugs which influence repaglinide metabolism. If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.Specific patient groupsNo 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.

Interactions
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, ketoconazole, 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 and repaglinide is contraindicated.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.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 can not 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.β-blocking agents 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 drugs that are mainly secreted by the bile, like repaglinide, any potential interaction should be considered.

Adverse Reactions
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 disordersVery rare: AllergyGeneralised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.Metabolism and nutrition disordersCommon: HypoglycaemiaNot known: Hypoglycaemic coma and hypoglycaemic unconsciousnessAs 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. Interactions with other medicinal products may increase the risk of hypoglycaemia. During post marketing experience, cases of hypoglycaemia have been reported in patients treated with repaglinide in combination with metformin or thiazolidinedione.Gastro-intestinal disordersCommon: Abdominal pain and diarrhoeaVery rare: Vomiting and constipationNot known: NauseaGastro-intestinal complaints such as abdominal pain, diarrhoea, nausea, vomiting and constipation have been reported in clinical trials. The rate and severity of these symptoms did not differ from that seen with other oral insulin secretagogues.Skin and subcutaneous tissue disordersNot known: HypersensitivityHypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no reason to suspect cross-allergenicity with sulphonylurea drugs due to the difference of the chemical structure.Eye disordersVery rare: Visual disturbancesChanges 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.Cardiac disordersRare: Cardiovascular diseaseType 2 diabetes is associated with an increased risk for cardiovascular disease. In one epidemiological study, a higher incidence of acute coronary syndrome was reported in the repaglinide group. However, the causality of the relationship remains uncertain.Hepato-biliary disordersVery rare: Hepatic function abnormalIn very rare cases, severe hepatic dysfunction has been reported. However, a causal relationship with repaglinide has not been established.Very rare: Increased liver enzymesIsolated cases of increase in liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increase in liver enzymes.

Manufacturer
Daiichi Sankyo UK Limited

Drug Availability
(POM)

Updated
12 August 2009