Instructions Amaryl tablets 4 mg blister No. 30
Composition
active ingredient: glimepiride;
1 tablet contains glimepiride 2 mg, or 3 mg, or 4 mg;
excipients:
2 mg tablets: lactose monohydrate, sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate, yellow iron oxide (E 172), indigo carmine aluminum lake (E 132);
3 mg tablets: lactose monohydrate, sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate, yellow iron oxide (E 172);
4 mg tablets: lactose monohydrate, sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate, indigo carmine aluminum lake (E 132).
Dosage form
Pills.
Main physicochemical properties:
2 mg tablets: green, oblong tablets, biplanar (with two flat surfaces) with a score line on both sides. Upper imprint*: NMM and Company logo; lower imprint*: Company logo and NMM;
3 mg tablets: pale yellow, oblong tablets, biplanar (with two flat surfaces) with a score line on both sides. Upper imprint*: NMN and Company logo; lower imprint*: Company logo and NMN;
4 mg tablets: light blue oblong tablets, biplanar (with two flat surfaces) with a score line on both sides. Upper embossment*: NMO and Company logo; lower embossment*: Company logo and NMO.
The tablet can be divided along the break line into equal doses.
* The order of embossing characters and the spatial placement of the stamp may vary.
Pharmacotherapeutic group
Hypoglycemic agents, except insulins. Sulfonamides, urea derivatives. ATX code A10B B12.
Pharmacological properties
Pharmacodynamics.
Glimepiride is an orally active hypoglycemic agent belonging to the sulfonylurea group. It can be used in non-insulin-dependent diabetes mellitus.
Glimepiride acts primarily by stimulating the release of insulin from pancreatic beta cells.
As with other sulfonylureas, this effect is based on an increase in the sensitivity of pancreatic cells to physiological stimulation by glucose. In addition, glimepiride has a pronounced extrapancreatic effect, which is also characteristic of other sulfonylureas.
Insulin release. Sulfonylureas regulate insulin secretion by closing the ATP-dependent potassium channel located in the membrane of the pancreatic beta cell. Closing the potassium channel causes depolarization of the beta cell and, by opening calcium channels, leads to an increase in calcium influx into the cell, which in turn leads to insulin release by exocytosis.
Glimepiride binds with a high rate of substitution to a beta-cell membrane protein associated with the ATP-dependent potassium channel, but the location of its binding site differs from the usual binding site of sulfonylureas.
Extrapancreatic activity. Extrapancreatic effects include, for example, improved sensitivity of peripheral tissues to insulin and reduced hepatic insulin utilization.
The utilization of blood glucose by peripheral tissues (muscle and adipose tissue) occurs with the help of special transport proteins located in the cell membrane. The transport of glucose into these tissues is limited by the speed of the glucose utilization step. Glimepiride very quickly increases the number of active molecules that transport glucose on the plasma membranes of muscle and adipose tissue cells, which leads to stimulation of glucose uptake.
Glimepiride increases the activity of glycosylphosphatidylinositol-specific phospholipase C, with which drug-induced lipogenesis and glycogenesis may be correlated in isolated muscle and fat cells.
Glimepiride inhibits hepatic glucose production by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis.
General characteristics. In healthy volunteers, the minimum effective oral dose was approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute exercise, i.e. a decrease in insulin secretion, is maintained under glimepiride.
No significant difference in the effect of glimepiride was found when the drug was taken 30 minutes before a meal or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours can be achieved when the drug is taken once a day.
Although the hydroxylated metabolite causes a small but significant decrease in blood glucose levels in healthy individuals, this is only a minor component of the overall effect of the drug.
Use in combination with insulin. Data on the use of the drug in combination with insulin are limited. In patients whose diabetes is not adequately controlled with maximum doses of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved the same improvement in metabolic control as insulin monotherapy; however, a lower average dose of insulin is required with combination therapy.
Special populations: Children, including adolescents: A 24-week active-controlled clinical trial (glimepiride up to 8 mg/day or metformin up to 2,000 mg/day) included 285 children (aged 8–17 years) with type 2 diabetes.
Both glimepiride and metformin resulted in significant reductions in HbA1c from baseline (glimepiride 0.95 (SD 0.41); metformin 1.39 (SD 0.40)). However, glimepiride was not shown to be more effective than metformin in terms of mean change from baseline in HbA1c. The difference between the two treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for this difference was not lower than the 0.3% non-inferiority margin.
No new safety concerns have been identified in children with glimepiride compared to adults with type 2 diabetes. Long-term efficacy and safety data are not available in children.
Pharmacokinetics.
Absorption. After oral administration, glimepiride is 100% bioavailable. Food intake has no significant effect on absorption, but only slightly slows down the rate of absorption. The maximum concentration of the drug in the blood serum (Cmax) is reached approximately 2.5 hours after oral administration of the drug (the average value is 0.3 μg / ml with multiple daily doses of 4 mg). There is a linear relationship between dose and Cmax, as well as dose and AUC (area under the concentration-time curve).
Distribution: Glimepiride has a very low volume of distribution (about 8.8 l), which is approximately equal to the volume of distribution of albumin, a high degree of binding to plasma proteins (more than 99%) and a low clearance (about 48 ml/min).
In animals, glimepiride is excreted in breast milk. Glimepiride crosses the placenta. Penetration across the blood-brain barrier is low.
Biotransformation and elimination: The mean terminal elimination half-life at plasma concentrations consistent with multiple dosing is approximately 5 to 8 hours. A slight increase in half-life has been observed following high doses.
After a single dose of radiolabeled glimepiride, 58% of the radioactivity was recovered in the urine and 35% in the feces. No unchanged substance was recovered in the urine. Two metabolites, most likely resulting from hepatic metabolism (primarily CYP2C9), were recovered in the urine and feces, one of which is a hydroxy derivative and the other a 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 pharmacokinetics after single and multiple once-daily dosing revealed no significant differences. Interindividual variability was very low. No significant accumulation was observed.
Special patient groups. Pharmacokinetic parameters in men and women, as well as in young and elderly subjects (over 65 years of age), were similar. In patients with reduced creatinine clearance, there was a tendency for glimepiride clearance to increase and its mean plasma concentration to decrease, which is most likely due to more rapid elimination due to a lower degree of protein binding. Renal excretion of both metabolites was impaired. In general, an increased risk of drug accumulation is not expected in these patients.
Pharmacokinetic parameters in five non-diabetic patients undergoing biliary tract surgery were similar to those in healthy volunteers.
Children, including adolescents: A study investigating the pharmacokinetics, safety and tolerability of a single dose of 1 mg glimepiride in the fed state in 30 children (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes mellitus demonstrated that mean AUC(0-last), Cmax and t1/2 were similar to those in adults.
Preclinical safety data. Effects observed in preclinical studies occurred at exposure levels well in excess of the maximum human exposure levels, indicating little relevance to clinical practice, or were due to the pharmacodynamic action of the drug (hypoglycemia). These results were obtained within the framework of conventional safety pharmacology studies, repeated dose toxicity studies, genotoxicity, carcinogenic potential and reproductive toxicity. Adverse effects observed in the latter (which included embryotoxicity, teratogenicity and developmental toxicity) were considered to be due to the hypoglycemic effects of the drug in dams and pups.
Indication
Type 2 diabetes in adults, if blood sugar levels cannot be controlled by diet, exercise and weight loss alone.
Contraindication
Amaryl® is not intended for the treatment of insulin-dependent diabetes mellitus, diabetic ketoacidosis, diabetic coma. The use of the drug is contraindicated in patients with severe renal or hepatic impairment. In case of severe renal or hepatic impairment, the patient should be transferred to insulin.
Amaryl® should not be taken by patients with hypersensitivity to glimepiride or to any of the excipients included in the preparation, to other sulfonylurea derivatives or sulfonamide drugs (risk of hypersensitivity reactions).
Interaction with other medicinal products and other types of interactions
The simultaneous use of Amaryl® with certain drugs can lead to both weakening and strengthening of the hypoglycemic effect of glimepiride. Therefore, other drugs should be taken only with the consent (or prescription) of a doctor. Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). It is known that this metabolism may be altered by the simultaneous use of inducers (e.g. rifampicin) or inhibitors of CYP2C9 (e.g. fluconazole). The results of an in vivo interaction study showed that fluconazole, one of the strongest inhibitors of CYP2C9, increases the AUC of glimepiride approximately twice.
Experience with Amaryl® and other sulfonylurea derivatives indicates the existence of the following types of interactions.
Potentiation of the blood glucose-lowering effect, and therefore in some cases hypoglycemia, may occur when glimepiride is taken simultaneously with the following drugs: phenylbutazone, azapropazone and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic drugs (such as metformin), some long-acting sulfonamides, tetracyclines, salicylates and p-aminosalicylic acid, MAO inhibitors, anabolic steroids and male sex hormones, quinolone antibiotics and clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high doses parenterally), fibrates, tritoqualine, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclo-, tro- and ifosfamides.
Weakening of the blood glucose-lowering effect and, accordingly, an increase in this level may occur when the patient simultaneously takes the following drugs: estrogens and progestogens; saluretics, thiazide diuretics; drugs that stimulate thyroid function, glucocorticoids; phenothiazine derivatives, chlorpromazine; adrenaline and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (long-term use); phenytoin, diazoxide; glucagon, barbiturates and rifampicin; acetazolamide. H2-receptor antagonists, beta-blockers, clonidine and reserpine can lead to both potentiation and weakening of the blood glucose-lowering effect.
Under the influence of sympatholytics, such as beta-blockers, clonidine, guanethidine and reserpine, the manifestations of adrenergic counterregulation of hypoglycemia may be reduced or disappear.
Alcohol consumption may increase or decrease the hypoglycemic effect of glimepiride in an unpredictable manner.
Glimepiride can both increase and decrease the effects of coumarin derivatives.
Colesevelam binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interactions were observed when glimepiride was taken at least 4 hours before colesevelam. Therefore, glimepiride should be taken at least 4 hours before colesevelam.
Application features
Amaryl® should be taken shortly before or during a meal.
In case of irregular meals or skipping meals, treatment with Amaryl® may cause hypoglycemia. Possible symptoms of hypoglycemia include headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disorders, increased motor activity, aggression, impaired concentration, anxiety and delayed reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, signs of adrenergic counterregulation may be present, such as sweating, cold and clammy skin, anxiety, tachycardia, arterial hypertension, increased heart rate, angina pectoris and cardiac arrhythmias.
The clinical presentation of a severe hypoglycemic attack may resemble that of a stroke.
Symptoms of hypoglycemia can almost always be quickly resolved by immediate consumption of carbohydrates (sugar). Artificial sweeteners are ineffective.
From the experience of using other sulfonylureas, it is known that, despite the initial effectiveness of measures to eliminate hypoglycemia, it may occur again.
Severe or prolonged hypoglycemia, which is only temporarily resolved by ordinary amounts of sugar, requires immediate treatment, sometimes hospitalization.
Factors contributing to the development of hypoglycemia include:
unwillingness or (especially in old age) inability of the patient to cooperate with the doctor;
malnutrition, irregular eating or skipping meals, or periods of fasting;
dietary violations;
alcohol consumption, especially in combination with skipping meals;
kidney dysfunction;
severe liver dysfunction;
overdose with Amaryl®;
certain decompensated endocrine diseases that affect carbohydrate metabolism or counterregulation of hypoglycemia (for example, in some thyroid disorders and insufficiency of the anterior pituitary or adrenal cortex);
simultaneous use of certain other medicines (see section "Interaction with other medicines and other types of interactions").
Treatment with Amaryl® requires regular monitoring of blood and urine glucose levels. In addition, it is recommended to determine the content of glycosylated hemoglobin.
During treatment with Amaryl®, liver function tests and hematological parameters (especially leukocyte and platelet counts) should be regularly monitored.
In stressful situations (e.g. trauma, unplanned surgery, infections accompanied by fever), temporary transfer of the patient to insulin may be indicated.
There is no experience with the use of Amaryl® in patients with severe hepatic impairment or in patients undergoing dialysis. Patients with severe renal or hepatic impairment should be switched to insulin.
Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylureas may lead to the development of hemolytic anemia. Since glimepiride belongs to the sulfonylurea class of drugs, it should be prescribed with caution to patients with glucose-6-phosphate dehydrogenase deficiency. They should be prescribed alternative drugs that do not contain sulfonylureas.
Amaryl® contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy. Risk associated with diabetes. Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Therefore, the blood glucose level of a pregnant woman should be carefully monitored to avoid teratogenic risk.
A pregnant woman with diabetes should be switched to insulin. Women with diabetes should inform their doctor about a planned pregnancy so that treatment can be adjusted and insulin can be switched.
Risk associated with glimepiride. There are no data on the use of glimepiride in pregnant women. According to the results of animal experiments, the drug has reproductive toxicity, probably related to the pharmacological action of glimepiride (hypoglycemia).
Therefore, glimepiride should not be used by women during the entire period of pregnancy.
If a patient taking glimepiride plans to become pregnant or becomes pregnant, she should be switched to insulin therapy as soon as possible.
Breastfeeding period.
It is not known whether the drug is excreted in human milk. In rats, glimepiride is excreted in breast milk. Since other sulfonylureas are excreted in breast milk and given the risk of hypoglycemia in breast-fed infants, breastfeeding is not recommended during glimepiride treatment.
The ability to influence the reaction speed when driving or working with other mechanisms
Studies on the effect of the drug on the ability to drive vehicles and work with other mechanisms have not been conducted.
The ability to concentrate and react may be impaired due to hypoglycaemia or hyperglycaemia or, for example, due to impaired vision. This may pose a risk in situations where this ability is particularly important (e.g. driving a car or operating other machinery).
Patients should be warned not to allow hypoglycemia to develop while driving. This is especially true for those who have poor or no ability to recognize the warning signs of hypoglycemia and those who have frequent hypoglycemic episodes. It is necessary to seriously consider whether to drive or operate machinery under these circumstances.
Method of administration and doses
The drug is intended for oral administration.
Successful treatment of diabetes depends on patients adhering to an appropriate diet, regular physical activity, and constant monitoring of blood and urine glucose levels. Failure to adhere to a diet cannot be compensated for by taking pills or using insulin.
The dosage depends on the results of blood and urine glucose tests.
The initial dose is 1 mg (1/2 tablet of 2 mg) of glimepiride per day. If this dose allows to control the disease, it should be used for maintenance therapy.
If glycemic control is not optimal, the dose should be increased to 2, 3 or 4 mg glimepiride per day in stages (at intervals of 1–2 weeks). The drug is available in different dosages for different treatment regimens.
If the maximum daily dose of metformin does not provide adequate glycemic control, concomitant therapy with glimepiride can be initiated.
Following the previous metformin dosage, glimepiride should be started at a low dose, which can then be gradually increased to the maximum daily dose, focusing on the desired level of metabolic control. Combination therapy should be carried out under close medical supervision.
If the maximum daily dose of Amaryl® does not provide adequate glycemic control, concomitant insulin therapy may be initiated if necessary. Following the previous glimepiride dosage, insulin treatment should be initiated at a low dose, which can then be increased, focusing on the desired level of metabolic control.
Combination therapy should be carried out under the close supervision of a physician.
Usually one dose of glimepiride per day is sufficient. It is recommended to take it shortly before or during a hearty breakfast or – if there is no breakfast – shortly before or during the first main meal. Errors in taking the drug, such as missing a dose, can never be corrected by taking a higher dose next time. The tablet should be swallowed without chewing, with liquid.
If a patient has a hypoglycemic reaction to glimepiride at a dose of 1 mg per day, this means that diabetes can be controlled only by following a diet.
Improved diabetes control is accompanied by increased insulin sensitivity, so during the course of treatment the need for glimepiride may decrease. In order to avoid hypoglycemia, the dose should be gradually reduced or therapy should be discontinued. The need for dosage adjustment may also arise if the patient's body weight or lifestyle changes or other factors that increase the risk of hypo- or hyperglycemia occur.
Switching from oral hypoglycemic agents to Amaryl®.
It is usually possible to switch from other oral hypoglycemic agents to Amaryl®. When switching, the potency and half-life of the previous agent should be taken into account. In some cases, especially if the antidiabetic agent has a long half-life (e.g. chlorpropamide), it is recommended to wait a few days before starting Amaryl®. This reduces the risk of hypoglycemic reactions due to the additive effect of the two agents.
The recommended starting dose is 1 mg glimepiride per day. As mentioned above, the dose can be gradually increased based on the response to the drug.
Switching from insulin to Amaryl®.
In exceptional cases, patients with type 2 diabetes who are taking insulin may be advised to switch to Amaryl®. Such a switch should be made under close medical supervision.
Children
There is currently no evidence for the use of glimepiride in patients under 8 years of age. For children aged 8 to 17 years, there is limited evidence for the use of glimepiride as monotherapy (see sections "Pharmacodynamics" and "Pharmacokinetics"). The existing data on the safety and efficacy of the drug in children are insufficient, therefore its use in this category of patients is not recommended.
Overdose
Overdose may result in hypoglycemia, which lasts from 12 to 72 hours and may recur after initial relief. Symptoms may appear 24 hours after administration. Clinical observation is generally recommended for such patients. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia may often be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, incoordination, drowsiness, coma, and convulsions.
Overdose treatment. Treatment consists primarily of preventing absorption of the drug. To do this, it is necessary to induce vomiting, and then drink water or lemonade with activated charcoal (adsorbent) and sodium sulfate (laxative). If a large amount of glimepiride has been taken, gastric lavage is indicated, followed by the use of activated charcoal and sodium sulfate. In case of severe overdose, hospitalization in the intensive care unit is necessary. Glucose administration should be started as soon as possible: if necessary, first a single intravenous injection of 50 ml of a 50% solution, and then an infusion of a 10% solution with constant monitoring of blood glucose levels. Further treatment is symptomatic.
When treating hypoglycemia caused by accidental ingestion of Amaryl® in infants and young children, the glucose dose should be adjusted particularly carefully due to the possibility of dangerous hyperglycemia, and its control should be carried out by careful monitoring of blood glucose levels.
Side effects
Based on experience with Amaryl® and other sulfonylureas, the following adverse reactions were observed during clinical trials, listed by system organ class in decreasing order of frequency: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10000 to <1/1000; very rare: <1/10000); frequency unknown (cannot be estimated from the available data).
Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia, which are usually reversible upon discontinuation of the drug. Frequency not known: severe thrombocytopenia with platelet count less than 10,000/µl and thrombocytopenic purpura.
From the immune system.
Very rare: leukocytoclastic vasculitis, moderate hypersensitivity reactions, which may progress to severe forms, accompanied by dyspnea, drop in blood pressure and sometimes shock.
Frequency unknown: possible cross-allergy with sulfonylurea derivatives, sulfonamides or related substances.
Metabolic and nutritional disorders.
Rare: hypoglycemia.
Such hypoglycaemic reactions are usually immediate, may be severe and may not always be easily corrected. The occurrence of such reactions, as with other hypoglycaemic agents, depends on individual factors such as dietary habits and dose (for details see section 4.4).
From the organs of vision.
Frequency unknown: Transient visual disturbances may occur, especially at the beginning of treatment, due to changes in blood glucose levels.
From the gastrointestinal tract.
Very rare: nausea, vomiting, diarrhea, bloating, abdominal discomfort, abdominal pain, which rarely lead to the need to discontinue treatment.
Hepatobiliary disorders.
Frequency unknown: increased liver enzymes.
Very rare: liver function abnormalities (e.g. with cholestasis or jaundice), hepatitis and hepatic failure.
On the skin and subcutaneous tissue.
Frequency unknown: Hypersensitivity reactions may occur, including itching, rash, urticaria, and photosensitivity.
Laboratory indicators.
Very rare: decreased serum sodium levels.
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions after the approval of a medicinal product by the regulatory authorities is an important procedure. It allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report all suspected adverse reactions via national reporting systems.
Expiration date
3 years.
Storage conditions
Keep out of reach of children. Store in original packaging at a temperature not exceeding +30 °C.
Packaging
No. 30 (15x2): 15 tablets in a blister, 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
SANOFI SRL/ SANOFI SRL
Address
SS 17 KM 22, SCOPPITO (AQ), 67019, Italy / SS 17 KM 22, SCOPPITO (AQ), 67019, Italy
Applicant
Sanofi-Aventis Ukraine LLC, Ukraine.
