INFORMATION FOR HEALTH PROFESSIONALS
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
NovoNorm 0.5 mg Tablet: White, round, convex tablet engraved with the Novo Nordisk logo (Apis bull). Each tablet contains 0.5mg of repaglinide.
NovoNorm 1mg Tablet: Yellow, round, convex tablet engraved with the Novo Nordisk logo (Apis bull). Each tablet contains 1mg of repaglinide.
NovoNorm 2mg Tablet: Peach, round, convex tablet engraved with the Novo Nordisk logo (Apis bull). Each tablet contains 2mg of repaglinide.
ATC code A 10 B X02
Repaglinide is a novel 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 beta cells in the pancreatic islets.
Repaglinide closes ATP-dependent 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 NovoNorm. 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 doses from 0.5 to 4 mg NovoNorm.
Clinical study results have indicated that NovoNorm 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.
Repaglinide is rapidly and completely absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the drug. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidly, and repaglinide is eliminated within 4 - 6 hours. The plasma elimination half-life is approximately one hour.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%), low volume of distribution, 30 L (consistent with distribution into intracellular fluid), and rapid elimination from the blood.
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.
Repaglinide 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 (2mg x3/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.
Repaglinide is highly bound to plasma proteins in humans (greater than 98%).
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.
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant hypoglycaemic effect have been identified.
Repaglinide and its 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 the parent drug is recovered in faeces.
NovoNorm (repaglinide) is an oral hypoglycaemic agent indicated for the treatment of Type 2 diabetes or Non-Insulin-Dependent Diabetes Mellitus (NIDDM) as a Prandial Glucose Regulator (PGR). NovoNorm treatment should be initiated when diet, physical exercise or weight reduction alone are not sufficient to control blood glucose levels.
NovoNorm is also indicated in combination with metformin or a thiazolidinedione for patients with Type 2 diabetes who are not satisfactorily controlled on one agent alone.
Repaglinide is given preprandially and is titrated individually to optimise the 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 NovoNorm may be sufficient during periods of transient loss of control in patients usually controlled well on diet.
NovoNorm should be taken before main meals.
The dosage should be determined by the physician, according to the patient's requirements.
The recommended starting dose is 0.5 mg, given with meals (preprandially).
About one to two weeks should elapse between titration steps (as determined by blood glucose response). If patients are transferred form another oral hypoglycaemic agent the recommended starting dose is 1 mg.
The maximum recommended single dose is 4 mg.
NovoNorm may be dosed preprandially two, three or four times a day in response to changes in the patient's meal pattern. Thus, the maximum total daily dose should not exceed 16 mg.
Repaglinide is primarily excreted via the bile and excretion is therefore not affected by renal disorders.
Only 8% 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.
In debilitated or malnourished patients, and patients with impaired hepatic function, the initial and maintenance dosage should be conservative to avoid hypoglycaemic reactions.
Patients can be transferred directly from other oral hypoglycaemic agents to NovoNorm. However, no exact dosage relationship exists between NovoNorm and the other oral hypoglycaemic agents. The maximum recommended starting dose of patients transferred to NovoNorm is 1 mg given just before main meals.
NovoNorm can be given in combination with metformin or a thiazolidinedione, when the blood glucose is insufficiently controlled with either agent alone. In this case, the dosage of metformin or the thiazolidinedione should be maintained and NovoNorm administered concomitantly. The starting dose of NovoNorm is 0.5 mg, taken before main meals; titration is according to blood glucose response as for monotherapy.
NovoNorm should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction.
NovoNorm, like most other oral hypoglycaemic agents, is capable of producing hypoglycaemia. Combination treatment is associated with an increased risk of hypoglycaemia.
The blood glucose lowering effect of any hypoglycaemic agent 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 should be assessed before classifying a patient as a secondary failure.
Repaglinide acts through a distinct binding site with a short action on the -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 clinical documentation of combination therapy with insulin is available. 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 NovoNorm and administer insulin on a temporary basis.
Findings from studies on combination therapy with thiazolidiones indicate that improved glycaemic control was correlated with increased weight gain.
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.
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 animals 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.
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
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)
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, 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 "Warnings and Precautions").
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.
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.
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.
Very rare: Increased liver enzymes
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, however, other causes were implicated in these cases and a causal relationship with repaglinide has not been established.
A number of drugs are known to influence glucose 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 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.
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketoconazole, trimethoprim, other antidiabetic agents, monoamine oxidase inhibitors (MAOI), non selective beta blocking agents, 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 to 3.7 hours resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide and plasma repaglinide concentration at 7 hours was increased 28.6-fold by gembribrozil, The concomitant use of gemfibrozil and repaglinide is contraindicated.
Co-administration of trimethoprim (160 mg twice daily), a weak CYP2C8 inhibitor, and repaglinide (a single dose of 0.25 mg) resulted in slight increases in 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.
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 one week after withdrawal of rifampicin where the inductive effect of rifampicin is no longer present.
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 1.5 fold and Cmax by 1.6 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 repaglinide AUC by 1.4 fold. No significant effect of 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.
β-blocking agents may mask the symptoms of hypoglycaemia.
Co-administration of cimetidine, oestrogen, nifedipine 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. Thus, dosage adjustment of digoxin, theophylline or warfarin 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 NovoNorm, the patient should be observed closely for loss of 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.
Repaglinide has been given with weekly escalating doses from 4 - 20 mg four times daily in a 6 week period. No safety concerns were raised. As hypoglycaemia in this study was avoided through increased calorie intake, a relative overdose may result in an exaggerated glucose lowering effect with development of hypoglycaemic symptoms (dizziness, sweating, tremor, headache etc.).
Should these symptoms occur, adequate action should be taken to correct the low blood glucose (oral carbohydrates). More severe hypoglycaemia with seizure, loss of consciousness or coma should be treated with i.v. glucose.
Store in a dry place between 15°C and 25°C.
Keep out of reach of children.
Prescription Medicine
Blister Packs: 30, 90 and 120 tablets
Microcrystalline cellulose (E460)
Calcium hydrogen phosphate, anhydrous
Maize starch
Polacrilin potassium
Polyvidone
Glycerol 85%
Magnesium stearate
Meglumine
Poloxamer
Iron oxide, yellow (1.0 mg tablets only) (E172)
Iron oxide, red (2.0 mg tablets only) (E172)
Aluminium/aluminium blister pack.
No special instructions
Novo Nordisk Pharmaceuticals
PO Box 51-268
Pakuranga
AUCKLAND
Tel: (09) 579 0653
Fax: (09) 579 0654
31 August 2004
SPC 5.04
NovoNorm is a trademark owned by Novo Nordisk A/S, Denmark