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Common name
Novonorm (Repaglinide)
Description
Novonorm (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.
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Active Ingredients:
Repaglinide
Therapeutic actions:
Novonorm (Repaglinide) is a novel short-acting oral secretagogue. Novonorm (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. In 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 drug concentrations were seen in the plasma of Type 2 diabetic patients 4 hours post-administration. A 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.
What is it used for?:
(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.
Contraindications and cautions:
Hypersensitivity to repaglinide or to any of the excipients in NovoNorm
• Type 1 diabetes (Insulin-Dependent Diabetes Mellitus: IDDM), C-peptide negative
• Diabetic ketoacidosis, with or without coma
• Pregnancy and lactation (Section 4.6)
• Children <12 years of age
• Severe hepatic function disorder
• Concomitant use of gemfibrozil (see section 4.5 Interaction with other medicinal products and other forms of interaction)
Special warnings and special precautions for use General 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 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. No trials of combination therapy with insulin or thiazolidenediones have been performed.
Combination treatment with metformin is associated with an increased risk of hypoglycaemia. 4 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.
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
Side effects:
Based on the experience with repaglinide and with other hypoglycaemic agents the following side effects have been seen: Frequencies are defined as: rare (> 1/10,000, <1/1,000) and very rare (<1/10,000) Metabolism and nutrition disorders Rare: Hypoglycaemia 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 further under 4.4 Special warnings and special precautions for use). During post marketing experience, cases of hypoglycaemia have been reported in patients treated with repaglinide in combination with metformin or thiazolidinedione. Gastro-intestinal disorders
Rare: Abdominal pain and nausea
Very rare: Diarrhoea, vomiting and constipation Gastro-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 disorders Rare: Allergy Hypersensitivity reactions of the skin may occur as itching, rashes and urticaria. There is no reason to suspect cross-allergenicity with sulphonylurea drugs due to the difference of the chemical structure.
Generalised hypersensitivity reactions, or immunological reactions such as vasculitis, may occur very rarely.
Eye disorders
Very rare: Visual disturbances 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.
Liver disorders
Very rare: Increased liver enzymes 6 Isolated 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.
In very rare cases, severe hepatic dysfunction has been reported.
Interactions:
A number of drugs are known to influence glucose metabolism, possible interactions should therefore be taken into account by the physician:
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketokonazole, 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, an inhibitor of CYP2C8, 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, 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 Contraindications).
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) by 15% and Cmax by 16%. Co-administration of 100 mg itraconazole has also been studied in healthy volunteers, and increased the AUC by 40%. 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 mechanism-based inhibitor of CYP3A4, increased the repaglinide (AUC) by 40% and Cmax by 67% and increased the mean incremental AUC of serum insulin by 51% and the maximum concentration by 61%. The exact mechanism of this interaction is not clear. β-blocking agents may mask the symptoms of hypoglycaemia.
Co-administration of other compounds that are metabolised by CYP3A4, such as cimetidine, nifedipine and oestrogen, did not significantly alter the absorption and disposition of repaglinide during multiple dosing in healthy subjects. In an interaction study in healthy volunteers, simvastatin did not alter the exposure to repaglinide, mean Cmax however, was increased by 25% with a very high variability (95% CI 0.95-1.68).
The clinical relevance of this finding is not clear. In an interaction study in healthy volunteers, rifampicin reduced the repaglinide (AUC) by 25%. The clinical relevance of this finding is not clear. 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, 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.
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