Amaryl

Amaryl

glimepiride

Manufacturer:

sanofi-aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Glimepiride.
Description
Each tablet contains the following excipients: Lactose monohydrate, sodium starch glycolate, magnesium stearate, microcrystalline cellulose, polyvidone 25000, red iron oxide (1 mg), yellow iron oxide (2 and 3 mg), indigo carmine aluminum lake (2 mg).
Action
Pharmacology: Pharmacotherapeutic Group: Oral blood glucose lowering drugs: Sulfonamides, urea derivatives. ATC Code: A10B B12.
Pharmacodynamics: Glimepiride is an orally active hypoglycaemic substance belonging to the sulfonylurea group. It may be used in non-insulin dependent diabetes mellitus (NIDDM).
Glimepiride acts mainly by stimulating insulin release from pancreatic β-cells.
As with other sulfonylureas, this effect is based on an increase of responsiveness of the pancreatic β-cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.
Insulin Release: Sulfonylureas regulate insulin secretion by closing the adenosine triphosphate (ATP)-sensitive potassium channel in the β-cell membrane. Closing the potassium channel induces depolarisation of the β-cell and results by opening of calcium channels in an increased influx of calcium into the cell.
This leads to insulin release through exocytosis.
Glimepiride binds with a high exchange rate to a β-cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulfonylurea binding site.
Extrapancreatic Activity: The 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 (GPI-PLC) 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.
General: In 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 min or immediately before a meal. In diabetic patients, good metabolic control over 24 hrs 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.
The time required to reach the maximum effect [ie, minimum blood glucose level (Tmin)] was about 2-3 hrs.
Combination Therapy With Metformin: Improved metabolic control for concomitant glimepiride therapy compared to metformin alone in patients not adequately controlled with the maximum dosage of metformin has been shown in 1 study.
Combination Therapy With Insulin: Data 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 2 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 Populations: Paediatric 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) with type 2 diabetes.
Both glimepiride and metformin exhibited a significant decrease from baseline in glycosylated hemoglobin (HbA1c) [glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.4)]. 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.
Pharmacokinetics: Absorption: The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approximately 2.5 hrs after oral intake (mean 0.3 mcg/mL during multiple dosing of 4 mg daily) and there is a linear relationship between dose and both Cmax and area under the concentration-time curve (AUC).
Distribution: Glimepiride has a very low distribution volume (approximately 8.8 L) which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approximately 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 Elimination: Mean dominant serum half-life (t½) which is of relevance for the serum concentrations under multiple-dose conditions is about 5-8 hrs. After high doses, slightly longer t½ were noted.
After a single dose of radiolabeled glimepiride, 58% of the radioactivity was recovered in the urine and 35% in the faeces. No unchanged substance was detected in the urine. Two (2) metabolites, most probably resulting from hepatic metabolism (major enzyme is CYP2C9), were identified both in urine and faeces: The hydroxy derivative and carboxy derivative. After oral administration of glimepiride, the terminal t½ of these metabolites were 3-6 and 5-6 hrs respectively.
Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics and the intraindividual variability was very low. There was no relevant accumulation.
Special populations: Pharmacokinetics were similar in males and females, as well as in young and elderly (>65 years) patients. In patients with low creatinine clearance (CrCl), 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 2 metabolites was impaired. Overall, no additional risk of accumulation is to be assumed in such patients.
Pharmacokinetics in 5 nondiabetic patients after bile duct surgery was similar to those in healthy persons.
Paediatric Population: A fed study investigating the pharmacokinetics, safety and tolerability of a single dose of glimepiride 1 mg in 30 paediatric patients (4 children 10-12 years and 26 children 12-17 years) with type 2 diabetes showed mean AUC(0-last), Cmax and t½ similar to that previously observed in adults.
Indications/Uses
Non-insulin dependent (type II) diabetes (NIDDM), whenever blood sugar levels cannot be controlled adequately by diet, physical exercise and weight reduction alone. Amaryl may also be used with an oral antidiabetic containing metformin or with insulin.
Dosage/Direction for Use
The basis for successful treatment of diabetes is a good diet, regular physical activity, as well as routine checks of blood and urine. Tablets or insulin cannot compensate if the patient does not keep to the recommended diet.
Dose is determined by the results of blood and urinary glucose determinations.
Starting Dose: 1 mg/day. If good control is achieved, this dose should be used for maintenance therapy. For the different dose regimens appropriate strengths are available. If control is unsatisfactory the dose should be increased, based on the glycaemic control, in a stepwise manner with an interval of about 1-2 weeks between each step to 2, 3 or 4 mg glimepiride per day.
A dose of >4 mg glimepiride per day gives better results only in exceptional cases. Maximum Recommended Dose: 6 mg/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 Amaryl, concomitant insulin therapy can be initiated if necessary. While maintaining the glimepiride dose, insulin treatment is started at 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 1st 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 glimepiride 1 mg 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 dose 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 Amaryl: A switch over from other oral hypoglycaemic agents to Amaryl can generally be done. For the switch over to Amaryl, the strength and the t½ of the previous medicine has to be taken into account. In some cases, especially in antidiabetics with a long t½ (eg, 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.
Recommended Starting Dose: 1 mg/day. Based on the response, the glimepiride dose may be increased stepwise, as indicated earlier.
Switch Over From Insulin to Amaryl: In exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to Amaryl may be indicated. The changeover should be undertaken under close medical supervision.
Special Populations: Renal or Hepatic Impairment: see Contraindications.
Administration: For oral administration.
Tablets should be swallowed without chewing with some liquid.
Overdosage
Symptoms: After ingestion of an overdose hypoglycaemia may occur, lasting from 12-72 hrs and may recur after an initial recovery. Symptoms may not be present for up to 24 hrs 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. Management: Treatment 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) overdose, hospitalisation in an intensive care department is indicated.
Start the administration of glucose as soon as possible, if necessary by a bolus IV injection of 50% solution 50 mL, 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 Amaryl 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.
Contraindications
Hypersensitivity to glimepiride, other sulfonylureas or sulfonamides or to any of the excipients of Amaryl.
Insulin dependent diabetes, diabetic coma, ketoacidosis, severe renal or hepatic function disorders. In case of severe renal or hepatic function disorders, a changeover to insulin is required.
Special Precautions
Amaryl must be taken shortly before or during a meal.
When meals are taken at irregular hours or skipped altogether, treatment with Amaryl may lead to hypoglycaemia. Possible symptoms of hypoglycaemia include: Headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, alertness and 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 and including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.
The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.
Symptoms can almost always be promptly controlled by immediate intake of carbohydrates (sugar).
Artificial sweeteners have no effect.
It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur.
Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar, require immediate medical treatment and occasionally hospitalisation.
Factors favouring hypoglycaemia include: Unwillingness or (more commonly in older patients) incapacity of the patient to cooperate; undernutrition, irregular mealtimes or missed meals or periods of fasting; alterations in diet; imbalance between physical exertion and carbohydrate intake; consumption of alcohol, especially in combination with skipped meals; impaired renal function; serious liver dysfunction; overdose with Amaryl; certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (eg, in certain disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency); concurrent administration of certain other medicinal products.
Treatment with Amaryl requires regular monitoring of glucose levels in blood and urine. In addition, determination of the proportion of glycosylated haemoglobin (HbA1c) is recommended.
Regular hepatic and haematological monitoring (especially leucocytes and thrombocytes) are required during treatment with Amaryl.
In stress-situations (eg, accidents, acute operations, infections with fever, etc) a temporary switch to insulin may be indicated.
No experience has been gained concerning the use of Amaryl in patients with severe impairment of liver function or dialysis patients. In patients with severe impairment of renal or liver function, change over to insulin is indicated. Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.
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 in pregnancy: Risk Related to The Diabetes: Abnormal 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 Glimepiride: There 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. 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.
Use in lactation: The 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.
Use in children: There are no data available on the use of glimepiride in patients <8 years. For children 8-17 years, there are limited data on glimepiride as monotherapy. The available data on safety and efficacy are insufficient in the paediatric population and therefore, such use is not recommended.
Use In Pregnancy & Lactation
Use in pregnancy: Risk Related to The Diabetes: Abnormal 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 Glimepiride: There 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. 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.
Use in lactation: The 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.
Adverse Reactions
The following adverse reactions from clinical investigations are based on experience with Amaryl and other sulfonylureas and are listed below by system organ class and in order of decreasing incidence: Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000), not known (cannot be estimated from the available data).
Metabolism and Nutrition Disorders: Rare: 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 eg, dietary habits and dose.
Eye Disorders: Not Known: Visual disturbances, transient, may occur especially on initiation of treatment, due to changes in blood glucose levels.
Gastrointestinal Disorders: Very Rare: Nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain, which seldom lead to discontinuation of therapy.
Blood and Lymphatic System Disorders: Rare: 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 <10,000/microliter and thrombocytopenic purpura.
Immune System Disorders: Very 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.
Hepatobiliary Disorders: Not Known: Increased hepatic enzymes. Very Rare: Abnormal hepatic function (eg, with cholestasis and jaundice), hepatitis and hepatic failure.
Skin and Subcutaneous Tissue Disorders: Not Known: Hypersensitivity reactions of the skin may occur as pruritus, rash, urticaria and photosensitivity.
Investigations: Very Rare: Decreased blood sodium.
Reporting of Suspected Adverse Reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the Amaryl. Health care professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
If glimepiride is taken simultaneously with certain other medicinal products, both undesired increases and decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicinal products should only be taken with the knowledge (or at the prescription) of the physician.
Glimepiride is metabolised by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be influenced by concomitant administration of CYP2C9 inducers (eg, rifampicin) or inhibitors (eg, fluconazole).
Results from in vivo interaction study reported in literature show that glimepiride AUC is increased approximately 2-fold by fluconazole, 1 of the most potent CYP2C9 inhibitors.
Based on experience with Amaryl and on what is known of other sulfonylureas, the following interactions must be considered.
Potentiation of the blood-glucose-lowering effect and thus, in some instances hypoglycaemia may occur when 1 of the following medicines is taken eg, phenylbutazone, azapropazone and oxyfenbutazone; insulin and oral antidiabetic products eg, metformin; salicylates and p-amino-salicylic acid; anabolic steroids and male sex hormones; chloramphenicol, certain long acting sulfonamides, tetracyclines, quinolone antibiotics and clarithromycin; coumarin anticoagulants; fenfluramine; disopyramide; fibrates; angiotensin-converting enzyme (ACE) inhibitors; fluoxetine, monoamine oxidase inhibitors (MAOIs); allopurinol, probenecid, sulfinpyrazone; sympatholytics; cyclophosphamide, trophosphamide and iphosphamides; miconazole, fluconazole; pentoxifylline (high dose parenteral); tritoqualine.
Weakening of the blood-glucose-lowering effect and thus, raised blood sugar levels may occur when one of the following medicines is taken eg, oestrogens and progestogens; saluretics, thiazide diuretics; thyroid stimulating agents, glucocorticoids; phenothiazine derivatives, chlorpromazine; adrenaline and sympathicomimetics; nicotinic acid (high doses) and nicotinic acid derivatives; laxatives (long-term use); phenytoin, diazoxide; glucagon, barbiturates and rifampicin; acetazolamide.
H2 antagonists, β-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
Under the influence of sympatholytic medicines such as β-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.
Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable fashion.
Glimepiride may either potentiate or weaken the effects of coumarin derivatives.
Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastrointestinal tract. No interaction was observed when glimepiride was taken at least for 4 hrs before colesevelam. Therefore, glimepiride should be administered at least 4 hrs prior to colesevelam.
Storage
Do not store above 30°C. Protect from moisture.
MIMS Class
ATC Classification
A10BB12 - glimepiride ; Belongs to the class of sulfonylureas. Used in the treatment of diabetes.
Presentation/Packing
Tab 1 mg (pink, oblong and scored on both sides) x 30's. 2 mg (green, oblong and scored on both sides) x 30's. 3 mg (pale yellow, oblong and scored on both sides) x 30's.
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