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Symglic supports "Pajacyk" program
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SUMMARY OF PRODUCT CHARACTERISTICSNAME OF THE MEDICINAL PRODUCT
Symglic tablets 1 mg QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 1 mg, 2 mg, 3 mg, 4 mg or 6 mg Glimepiridum (glimepiride). For excipients see section 6.1. PHARMACEUTICAL FORM
Tablets 1 mg are pink, oblong and scored on both sides.
CLINICAL PARTICULARS
Symglic is indicated for the treatment of type 2 diabetes mellitus when diet, physical exercise and weight reduction are not effective enough.
For oral administration. Dosage is determined by the results of blood and urinary glucose determinations. A dose of more than 4 mg glimepiride daily gives better therapeutic results only in exceptional cases. The maximum recommended dose is 6 mg glimepiride daily. In patients in whom the maximum daily dose of metformin has not resulted in satisfactory results, concomitant glimepiride therapy can be used. While maintaining the metformin dose, glimepiride therapy should be started with a low dose, which is then titrated up depending on the desired level of glucose concentration, up to the maximum daily dose. The combination therapy should be initiated under close supervision of the doctor. In patients in whom the maximum daily dose of Symglic preparation has not resulted in satisfactory results, concomitant insulin therapy can be initiated if necessary. While maintaining the dose of glimepiride, insulin treatment should be started at low dose and titrated up depending on the desired level of glucose concentration. The combination therapy should be initiated under close supervision of the doctor. Usually a single daily dose of glimepiride is sufficient. It is recommended to take the drug shortly before or during a substantial breakfast or if none has been taken – shortly before or during the first main meal. If a hypoglycaemic reaction occurs in the patient on 1 mg glimepiride daily, this indicates that glycaemia can be controlled by diet alone. In the course of treatment, as an improvement in control of diabetes is associated with higher insulin sensitivity, demand for glimepiride may decrease. To avoid hypoglycaemia, timely dose reduction or discontinuation of the drug must be considered. The change in dosage may also be necessary if there are changes in body weight or life style of the patient, or other factors that increase the risk of hypo- or hyperglycaemia.
The change of treatment method is generally possible by replacing other oral antidiabetic drugs with Symglic preparation. For the switch of the treatment to Symglic, the dosage and the half-life of the previous drug has to be taken into account. In some medicines, especially in case of antidiabetic drugs with a long half-life (e.g. chlorpropamide), a wash out period of a few days is advisable in order to minimize the risk of hypoglycaemic reactions due to the additive effect. The recommended starting dose of glimepiride is 1 mg daily.
In exceptional cases, in patients with type 2 diabetes mellitus treated with insulin, a switch over to Symglic may be indicated. The switch over should be undertaken under close supervision of the doctor.
See section 4.3. The preparation is available in doses adjusted to various treatment schedules.
Symglic preparation should not be used in the following cases:
In case of severe renal or hepatic function disorder, a change over to insulin is required. Using glimepiride in pregnancy and lactation is contraindicated.
Symglic should be taken shortly before or during a meal. When meals are taken at irregular hours or skipped altogether, the treatment with Symglic preparation may lead to hypoglycaemia. Possible symptoms of hypoglycaemia are as follows: headache, ravenous hunger, nausea, vomiting, weariness, sleepiness, sleep disorders, restlessness, aggressiveness, impaired concentration, alertness and reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, feeling of helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness including coma, shallow respiration and bradycardia. Moreover, symptoms of adrenergic regulation disorder may appear such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias. The clinical picture in a severe hypoglycaemia may resemble that of a stroke. The above symptoms can be usually promptly controlled by immediate administration of carbohydrates (sugar). Artificial sweeteners are ineffective. Severe or prolonged hypoglycaemia, only temporarily corrected by the intake of usual amounts of sugar, requires immediate pharmacological treatment and occasionally hospitalization. Factors that may have an influence on the development of hypoglycaemia include:
Treatment with Symglic preparation requires regular monitoring of sugar levels in blood and the urine. In addition, determination of glycosylated haemoglobin is recommended. Regular monitoring of hepatic function and haematological picture (especially of the number of leucocytes and thrombocytes) are required during the treatment with Symglic preparation. In stressful situations (e.g. accidents, emergency operations, infections with fever, etc.) a temporary switch over to insulin may be indicated. No experiments regarding the use of glimepiride in patients with severe impairment of liver function or dialyzed patients have been performed. In patients with severe impairment of renal or liver function a switch over to insulin is indicated. Symglic preparation includes lactose. Patients with rare hereditary disorders such as galactose-intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, should not use this medicine. Symglic 6 mg, tablets:
If Symglic is taken concomitantly with certain other medicines, increases as well as decreases in the hypoglycaemic action of glimepiride may occur. Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Glimepiride metabolism is known to be influenced by concomitant administration of inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of enzyme CYP2C9. Results from an in-vivo interaction study reported in literature show that the area under the curve (AUC) for glimepiride is increased approximately by 2-fold by fluconazole, one of the most potent CYP2C9 inhibitors. Interactions are described on the basis of the experience with the use of glimepiride and other sulfonylurea derivatives. Potentiation of the blood-sugar-lowering effect, in some cases leading to hypoglycaemia, may occur as a result of concomitant administration of Symglic preparation with one of the following active substances:
Weakening of the blood-sugar-lowering effect and, thus raised blood sugar concentration may occur when Symglic preparation is administered with one of the following active substances, e.g.:
H2 receptor antagonists, beta-adrenergic receptor blockers, clonidine and reserpine may lead to potentiation as well as weakening of the hypoglycaemic effect. Both single and prolonged alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable way. Glimepiride may either potentiate or weaken the effects of coumarin derivatives.
Pregnancy Diabetes-related risk Glimepiride-related risk Therefore, glimepiride is contraindicated in the whole pregnancy period. Lactation It is not known whether the medicine passes into the breast milk. Glimepiride is secreted into milk in rats. Because other sulfonylurea derivatives pass into the breast milk, and because there is a risk of developing hypoglycaemia in breast-fed babies, glimepiride must not be taken during breast-feeding period.
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of disorders of vision. This may constitute a risk in situations where these abilities are of particular importance (e.g. driving a car or operating machinery). Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those patients who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether in these circumstances driving or operating machinery is advisable.
Based on the use of glimepiride and other sulfonylurea derivatives, the following undesirable effects have occurred: Undesirable effects have been classified in order of frequency using the following convention: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000 <1/1,000), very rare (<1/10,000), including single cases. Blood and lymphatic system disorders Immune system disorders Metabolism and nutrition disorders These reactions mostly occur immediately, may be severe and are not always easy to correct. The occurrence of such reactions depends, as with other antidiabetic therapies, on individual factors such as dietary habits and the dosage (see section 4.4.). Eye disorders Gastrointestinal disorders Hepato-biliary disorders Skin and subcutaneous tissue disorders Influence on laboratory tests results
After overdosage hypoglycaemia lasting from 12 to 72 hours may occur, which may recur after an initial recovery. Symptoms may not appear for up to 24 hours after ingestion. In most cases observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, co-ordination problems, sleepiness, coma and convulsions. At the beginning the treatment consists of preventing absorption by administering activated charcoal (adsorbent) and sodium sulphate (laxative). If large quantities of the medicine have been ingested, gastric lavage is indicated, followed by the administration of activated charcoal and sodium sulphate. In case of (particularly severe) overdosage, hospitalization in an intensive care department is indicated. The administration of glucose should be started as soon as possible, if necessary by an intravenous injection of 50 ml of a 50% solution (bolus), followed by an infusion of a 10% solution with strict monitoring of blood glucose concentration. Further treatment should be symptomatic. In particular cases, when treating hypoglycaemia due to accidental intake of Symglic preparation in infants and young children, the dose of glucose administered must be carefully controlled to avoid the possibility of danger of developing hyperglycaemia. Blood glucose should be carefully monitored. PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: oral antidiabetic drugs: sulfonamides, urea derivatives. Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells. As with other sulfonylurea derivatives, this effect is based on an increase in responsiveness of the pancreatic beta cells to the physiological glucose stimulus. Besides, glimepiride reveals a visible extrapancreatic effect also postulated for other sulfonylurea derivatives.
Sulfonylurea derivatives regulate insulin secretion by closing the ATP-dependent potassium channel in the beta cell membrane of the pancreas. Closing the potassium channel induces depolarization of the membrane of the beta cell and leads – by opening of calcium channels – to an increased influx of ions of calcium into the cell. This leads to insulin release as a result of exocytosis. Glimepiride binds reversibly to a beta cell membrane protein which is associated with the ATP-dependent potassium channel, but the binding site is different from the usual sulfonylurea derivatives binding site.
The extrapancreatic activity includes e.g. an improvement of the sensitivity of the peripheral tissues to insulin and a decrease of the insulin uptake by the liver. The uptake of glucose from blood through peripheral muscle and fat tissues takes place via special transport proteins, located in the cells membrane. The transport of glucose in these tissues is the stage that limits the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the cell membranes of muscles and fat tissue, which results in increased 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 turn inhibits the gluconeogenesis.
In healthy persons, the minimum effective oral dose is approximately 0,6 mg. The effect of glimepiride is determined on the dose and is reproducible. The physiological response to acute physical exercise, in the form of reduction of insulin secretion, is still present during the administration of glimepiride. There were no significant differences in effect of the drug given 30 minutes or immediately before a meal. In diabetic patients, satisfactory metabolic control is maintained for 24 hours after the administration of a single daily dose.
Improvement in metabolic control for combination glimepiride therapy compared to metformin alone in patients not adequately controlled with the maximum daily dosage of metformin has been shown in one study.
Data regarding combination therapy with insulin are limited. In patients not adequately controlled with the maximum dosage of glimepiride, concomitant therapy with insulin 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.
In animals, glimepiride is excreted in milk. Glimepiride passes into the placenta. Passage of the blood brain barrier is low.
After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. Unchanged substance was not detected in the urine. Two metabolites were identified both in urine and faeces – most probably resulting from hepatic changes (mainly by CYP2C9) – 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.
Pharmacokinetics was similar in males and females, as well as in young and elderly (over 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 as a result of a more rapid elimination because of lower protein binding. Renal elimination of the two metabolites was decreased. Generally no additional risk of accumulation of the drug is to be expected in such patients. Pharmacokinetics in five non-diabetic patients after bile duct surgery was similar to those in healthy persons.
Preclinical tests results observed during the period of administration of the doses sufficiently in excess of the maximum human doses have little relevance to clinical use, or were resulted from the pharmacodynamic activity (hypoglycaemia) of the active substance. These results are based on conventional safety pharmacological studies, repeated dose toxicity studies, genotoxicity, carcinogenicity, and reproduction toxicity studies. In the latter (covering embryotoxicity, teratogenicity and developmental toxicity), undesirable effects observed were considered to be secondary to the hypoglycaemic effects induced by the active substance in dams and in offspring. PHARMACEUTICAL PARTICULARS
lactose monohydrate Tablets 1 mg contain the colorant: red iron oxide (E172).
Not applicable.
2 years
None.
Transparent PVC/Aluminium foil blisters in a cardboard box. Pack sizes: 10, 20, 30, 50, 60, 90 or 120 tablets (in blisters, 10 tablets each).
None.
MARKETING AUTHORISATION NUMBERS 1 mg – 12071 dated 13th February 2006
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