Summary of Product Characteristics Updated 09-Sep-2014 | Accord Healthcare Limited
PosologyThe dosage is determined by the results of blood and urinary glucose determinations.The starting dose is 1 mg glimepiride per day. If good control is achieved, this dosage should be used for maintenance therapy.For the different dosage regimens appropriate strengths are available.If control is unsatisfactory, the dosage should be increased, based on the glycaemic control, in a stepwise manner with an interval of about 1 to 2 weeks between each step, to 2, 3, or 4 mg glimepiride per day. A dosage of more than 4 mg glimepiride per day gives better results only in exceptional cases.The maximum recommended dose is 6 mg glimepiride per day.In patients not adequately controlled with the maximum daily dose of metformin, concomitant glimepiride therapy can be initiated. While maintaining the metformin dose, the glimepiride therapy is started with a low dose, and is then titrated up depending on the desired level of metabolic control up to the maximum daily dose. The combination therapy should be initiated under close medical supervision.In patients not adequately controlled with the maximum daily dose of glimepiride, concomitant insulin therapy can be initiated if necessary. While maintaining the glimepiride dose, insulin treatment is started at a low dose and titrated up depending on the desired level of metabolic control. The combination therapy should be initiated under close medical supervision.Normally a single daily dose of glimepiride is sufficient. It is recommended that this dose be taken shortly before or during a substantial breakfast or - if none is taken - shortly before or during the first main meal. If a dose is forgotten, this should not be corrected by increasing the next dose. If a patient has a hypoglycaemic reaction on 1 mg glimepiride daily, this indicates that they can be controlled by diet alone.In the course of treatment, as an improvement in control of diabetes is associated with higher insulin sensitivity, glimepiride requirements may fall. To avoid hypoglycaemia timely dose reduction or cessation of therapy must therefore be considered. Change in dosage may also be necessary if there are changes in weight or life style of the patient, or other factors that increase the risk of hypo- or hyperglycaemia.
Switch over from other oral hypoglycaemic agents to glimepirideA switch over from other oral hypoglycaemic agents to glimepiride can generally be done. For the switch over to glimepiride the strength and the half-life of the previous medicinal product has to be taken into account. In some cases, especially in antidiabetics with a long half-life (e.g. chlorpropamide), a wash out period of a few days is advisable in order to minimise the risk of hypoglycaemic reactions due to the additive effect. The recommended starting dose is 1 mg glimepiride per day. Based on the response the glimepiride dosage may be increased stepwise, as indicated earlier.
Switch over from insulin to glimepirideIn exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to glimepiride may be indicated. The changeover should be undertaken under close medical supervision.
Patients with renal or hepatic impairmentSee section 4.3.
Paediatric populationThere are no data available on the use of glimepiride in patients under 8 years of age. For children aged 8 to 17 years, there are limited data on glimepiride as monotherapy (see sections 5.1 and 5.2).The available data on safety and efficacy are insufficient in the paediatric population and therefore such use is not recommended.
Method of administrationTablets should be swallowed without chewing with some liquid.
PregnancyRisk related to the diabetesAbnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities and perinatal mortality. So the blood glucose level must be closely monitored during pregnancy in order to avoid the teratogenic risk. The use of insulin is required under such circumstances. Patients who consider pregnancy should inform their physician.
Risk related to glimepirideThere are no adequate data from the use of glimepiride in pregnant women. Animal studies have shown reproductive toxicity which likely was related to the pharmacologic action (hypoglycaemia) of glimepiride (see section 5.3).Consequently, glimepiride should not be used during the whole pregnancy. In case of treatment by glimepiride, if the patient plans to become pregnant or if a pregnancy is discovered, the treatment should be switched as soon as possible to insulin therapy.
LactationThe excretion in human milk is unknown. Glimepiride is excreted in rat milk. As other sulfonylureas are excreted in human milk and because there is a risk of hypoglycaemia in nursing infants, breast-feeding is advised against during treatment with glimepiride.
Blood and lymphatic system disordersRare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia, which are in general reversible upon discontinuation of medication. Not known: severe thrombocytopenia with platelet count less than 10,000/µl and thrombocytopenic purpura.
Immune system disordersVery rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with dyspnoea, fall in blood pressure and sometimes shock. Not known: cross-allergenicity with sulfonylureas, sulfonamides or related substances is possible.
Metabolism and nutrition disordersRare: hypoglycaemia.These hypoglycaemic reactions mostly occur immediately, may be severe and are not always easy to correct. The occurrence of such reactions depends, as with other hypoglycaemic therapies, on individual factors such as dietary habits and dosage (see further under section 4.4).
Eye disordersNot known: visual disturbances, transient, may occur especially on initiation of treatment, due to changes in blood glucose levels.
Gastrointestinal disordersVery rare: nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain, which seldom lead to discontinuation of therapy.
Hepato-biliary disordersVery rare: hepatic function abnormal (e.g. with cholestasis and jaundice), hepatitis and hepatic failure.Not known: hepatic enzymes increased.
Skin and subcutaneous tissue disordersNot known: hypersensitivity reactions of the skin may occur as pruritus, rash, urticaria and photosensitivity.
InvestigationsVery rare: blood sodium decrease.
Reporting of suspected adverse reactionsReporting 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 at: www.mhra.gov.uk/yellowcard.
SymptomsAfter ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72 hours, and may recur after an initial recovery. Symptoms may not be present for up to 24 hours after ingestion. In general observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be accompanied by neurological symptoms like restlessness, tremor, visual disturbances, co-ordination problems, sleepiness, coma and convulsions.ManagementTreatment primarily consists of preventing absorption by inducing vomiting and then drinking water or lemonade with activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested gastric lavage is indicated, followed by activated charcoal and sodium-sulphate. In case of (severe) overdosage hospitalisation in an intensive care department is indicated. Start the administration of glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of a 50% solution, followed by an infusion of a 10% solution with strict monitoring of blood glucose. Further treatment should be symptomatic.In particular when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be carefully controlled to avoid the possibility of producing dangerous hyperglycaemia. Blood glucose should be closely monitored.
|Pharmacotherapeutic group||: Blood glucose lowering drugs, excl. insulins: Sulfonamides, urea derivatives|
|ATC Code||: A10B B12|
Extrapancreatic activityThe extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins, located in the cells membrane. The transport of glucose in these tissues is the rate limiting step in the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase C, which may be correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2,6-bisphosphate, which in its turn inhibits the gluconeogenesis.
GeneralIn healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion, is still present under glimepiride.There was no significant difference in effect regardless of whether the medicinal product was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single daily dose. Although the hydroxy metabolite of glimepiride caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total drug effect
Combination therapy with metforminImproved metabolic control for concomitant glimepiride therapy compared to metformin alone in patients not adequately controlled with the maximum daily dosage of metformin has been shown in one study.
Combination therapy with insulinData for combination therapy with insulin are limited. In patients not adequately controlled with the maximum dosage of glimepiride, concomitant insulin therapy can be initiated. In two studies, the combination achieved the same improvement in metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.
Special populationsPaediatric population:An active controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 285 children (8-17 years of age) with type 2 diabetes.Both glimepiride and metformin exhibited a significant decrease from baseline in HbA1c (glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.40)). However, glimepiride did not achieve the criteria of non-inferiority to metformin in mean change from baseline of HbA1c. The difference between treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for the difference was not below the 0.3% non-inferiority margin.Following glimepiride treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.
AbsorptionThe bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only the absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approx 2.5 hours after oral intake (mean 0.3 μg/ml during multiple dosing of 4 mg/daily) and there is a linear relationship between dose and both Cmax and AUC (area under the time concentration curve).
DistributionGlimepiride has a very low distribution volume (approx. 8.8 litres), which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min).In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood-brain barrier is low.
Biotransformation and eliminationMean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites most probably resulting from hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3 to 6 and 5 to 6 hours respectively. Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intra individual variability was very low. There was no relevant accumulation.
Special populationsPharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding. Renal elimination of the two metabolites was impaired. Overall no additional risk of accumulation is to be assumed in such patients.Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.Paediatric populationA fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of glimepiride in 30 paediatric patients (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes showed mean AUC(0-last) , Cmax and t1/2 similar to that previously observed in adults.
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