AMARYL Tablet

Amaryl is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with typeⅡdiabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone.

Amaryl may be used concomitantly with metformin, when diet, exercise and Amaryl or Metformin alone do not result in adequate glycemic control.

Amaryl is also indicated for used in combination with insulin to lower the blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent. Combined used of glimepiride and insulin may increase the potential for hypoglycemia.

Dosage

In principle, the dosage of Amaryl is governed by the desired blood sugar level. The dosage of glimepiride must be the lowest which is sufficient to achieve the desired metabolic control.

Treatment with Amaryl must be initiated and monitored by a doctor. Amaryl must be taken at the times and in the doses prescribed. Mistakes, e.g. forgetting to take a dose, must never be corrected by subsequently taking a larger dose.

Measure for dealing with such mistakes (in particular forgetting a dose or skipping a meal) or situations where a dose cannot be taken at the prescribed time must be discussed and agreed between doctor and patient before-hand. A doctor must be notified immediately if the dose taken is too high, or an extra dose has been taken.

The initial and the maintenance doses are set based on the result of regular checks of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy.

Initial dose and dose titration: The usual initial dose is 1mg Amaryl once daily. If necessary, the daily dose can be increased. Any increase should be based on regular blood sugar monitoring, and should be gradual, i.e. at intervals of 1-2 weeks, and carried out stepwise, as follows:

1mg-2mg-3mg-4mg, and -in exceptional cases - 8mg.

Dose range in patients with well controlled diabetes: The usual dose range in patients with well controlled diabetes is 1-4mg Amaryl daily. Only some patients benefit from daily doses of more than 6mg.

Distribution of doses: Timing and distribution of doses are decided by the doctor, taking into consideration of the patient’s current life-style. Normally, a single daily dose of Amaryl is sufficient. This dose should be taken immediately before a substantial breakfast of if none is taken immediately before the first main meal. It is very important not to skip meals after taking Amaryl.

Secondary dosage adjustment: As the control of diabetes improves, sensitivity to insulin increases; therefore, glimepiride requirements may fall as treatment proceeds. To avoid an excessive reduction in blood sugar (hypoglycaemia) a timely dose reduction or of Amaryl therapy must be considered.

A dose adjustment must also be considered whenever the patient’s weight of life-style changes, or other factors causing an increased susceptibility to hypoglycaemia or to an excessive increase in blood sugar levels (hyperglycaemia) arise.

Duration of treatment: Treatment with Amaryl is normally a long-term therapy. Changeover from other oral antidiabetics to Amaryl: There is no exact dosage relationship between Amaryl and other oral blood-sugar-lowering agent. When substituting Amaryl for other such agents, the initial daily dose is 1mg; this applies even in changeovers from the maximum dose of another oral blood sugar lowering agent. Any Amaryl dose increase should be in accordance with guidelines given above in “Initial dose and dose titration”.

Consideration must be given to the potency and duration of action of the previous blood-sugar-lowering agent. It may be necessary to interrupt treatment to avoid additive effects which would increase the risk of hypoglycaemia. Use in combination with metformin:

Whenever blood sugar levels cannot be controlled adequately with the maximum daily dose of either Amaryl or a metformin-containing antidiabetic alone, both medicines may be used concomitantly. In such cases, the dose of the established medicine remains unchanged. Treatment with the additional medicine is started at a low dose. Combined treatment should be initiated under close medical supervision.

Use in combination with insulin: Whenever blood sugar levels cannot be controlled adequately with the maximum daily dose of Amaryl, insulin may be given concomitantly. In this case, the current dose of Amaryl remains unchanged. Insulin treatment is started at a low dose, which is subsequently increased stepwise according to the desired blood sugar level. Combined treatment should be initiated under close medical supervision.

Long term efficacy should be monitored by measurement of HbA1c levels, for example every 3-6 months.

Short term administration of Amaryl may be sufficient during periods of transient loss of control in patients usually controlled well on diet and exercise.

There is limited information available on the use of Amaryl in renal insufficiency. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of Amaryl.

ADMINISTRATION

Amaryl tablets must be swallowed without chewing and with sufficient amounts of liquid (approx.. 1/2 glass).

Amaryl is not suitable for the treatment of insulin-dependent (type1) diabetes mellitus (e.g. for the treatment of diabetics with a history of ketoacidosis), of diabetic ketoacidosis, or of diabetic precoma or coma.

Amaryl must not be used in patients hypersensitive to glimepiride, other sulfonylureas, other sulfonamides, or any of the excipients.

No experience has been gained concerning the use of Amaryl in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of renal or hepatic function, a changeover to insulin is indicated, not least to achieve optimal metabolic control.

Based on experience with Amaryl and on what is known of other sulfonylureas, the following adverse effects must be considered:

(See the package insert about the details)

Hypoglycaemia

Eyes

Digestive tract

Blood

Since some adverse effects (e.g. severe hypoglycaemia, certain changes, in blood picture, severe allergic or pseudo allergic reactions, or liver failure) may under certain circumstances become life-threatening, it is essential that, if sudden or severe reactions do occur, you inform a doctor at once, and on no account continue taking the drug without a doctor’s express guidance.

Further to the above-mentioned adverse effect of Amaryl, the following events have been reported with sulfonylureas:

 Porphyria cutanea tarda

 Hepatic porphyria reaction

 Disulfiram-like reaction

 Syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

It has been suggested that these sulfonyl ureas may augment the peripheral action of ADH and/or increase release of ADH.

Patients who take or discontinue taking certain other medicines while undergoing treatment with Amaryl may experience changes in blood sugar control.

Based on experience with Amaryl and on what is known of other sulfonylureas, the following interactions must be considered:

Glimepiride is metabolized by CYP2S9. This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) or CYP2C9.

Potentiation of the blood-sugar-lowering effect and thus, in some instances hypoglycaemia may occur when one of the following medicines is taken, for example: insulin and other oral anti-diabetics, ACE inhibitors, allopurinol anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (high dose parenteral), phenylbutazone, azopropazone, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, clarithromycin, sulfonamides, tetracyclines, tritoqualine, trofosfamide.

Weakening of the blood-sugar-lowering effect and, thus, raised blood sugar levels may occur when one of the following medicines is taken, for example: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) and other sympathomimetic agents, glucagons, laxatives (after protacted use), nicotinic acid (in high doses), oestrogens and progestogens, phenothiazines, phenytoin, rifampicin, thyroid hormones.

H2 receptor antagonists, clonidine and reserpine may lead to either potentiation or weakening of the blood-sugar-lowering effect.

Beta-blockers decrease glucose tolerance. In patients with diabetes mellitus, this may lead to deterioration of metabolic control. In addition, beta-blockers may increase the tendency to hypoglycaemia (due to impaired counter regulation).

Under the influence of sympatholytic medicine such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.

Both acute and chronic alcohol intake may potentiate or weaken the blood-sugar-lowering action of Amaryl unpredictably.

The effect of coumarin derivatives may be potentiated or weakened.

To avoid risk of harm to the child, Amaryl must not be taken during pregnancy; a changeover to insulin is necessary.

Patients planning a pregnancy must inform their doctor, and should change over to insulin. Ingestion of glimepiride with the breast milk may harm the child. Therefore, Amaryl must not be taken by breast-feeding women and a changeover to insulin or discontinuation of breast-feeding is necessary.

To achieve optimal control of blood sugar, a correct diet, regular and sufficient physical exercise and, if necessary, reduction of body weight are just as important as regular intake of Amaryl. Clinical signs of hyperglycaemia are e.g. increased urinary frequency, intense thirst, dryness of the mouth, and dry skin. When starting treatment, the patients must be informed about the effects and risks of Amaryl and about its role in conjunction with dietary measures and physical exercise; the importance of adequate cooperation must also be stressed.

In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring. Factors favouring hypoglycaemia include:

 unwillingness or (more commonly in older patients) incapacity of the patients to cooperate,

 under nutrition, irregular meal-times, or skipped meals,

 imbalance between physical exertion and carbohydrate intake,

 alterations of diet,

 consumption of alcohol, especially in combination with skipped meals,

 impaired renal function,

 severe impairment of liver function,

 overdosage with Amaryl,

 certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency),

 concurrent administration of certain other medicines.

The doctor must be informed about such factors and about hypoglycaemic episodes, since these require particularly careful monitoring.

If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of Amaryl or the entire therapy. This also applies whenever illness occurs during therapy or the patient’s life-style changes.

Those symptoms of hypoglycaemia which reflect the body’s adrenergic counter-regulation may be milder or absent in those situations where hypoglycaemia develops gradually, in the elderly, and in patients with a certain type of nervous disease (autonomic neuropathy) or those receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine, or other sympatholytic drugs.

Hypoglycaemia can almost always be promptly controlled by immediate intake of sugar, e.g., in the form of glucose, sugar cubes or sugar sweetened beverages. Patients should always carry at least 20g of glucose with them for this purpose (food or beverages containing artificial sweeteners - such as diet foods or drinks are ineffective in controlling hypoglycaemia). They may require the assistance of other persons to avoid complications. It is known from other sulfonylureas that, despite initially successful counter-measures, hypoglycaemia may recur.

Therefore, continued close observation is necessary. Severe hypoglycaemia requires, in addition, immediate treatment and follow-up by a doctor and in some circumstances, hospitalization.

It treated by different doctor (upon e.g. admission to hospital after an accident, illness while on holiday), the patients must inform them of their diabetic condition ad previous treatment.

In exceptional stress situations (e.g. trauma, surgery, infections with fever) blood sugar control may deteriorate, and a temporary change to insulin may be necessary.

During treatment with Amaryl, fasting glucose levels in blood and urine must be checked regularly, as should, additionally, the proportion of glycosylated haemoglobin. Usually every 3-6 months to more precisely assess long term glycemic control.

Pediatric use: safety and effectiveness in pediatric patients have not been established.

Alertness and reactions may be impaired due to hypo-or-hyperglycaemia, especially when beginning or after alerting treatment, or when Amaryl is not taken regularly. Such impairment may, for example, affect the ability to operate a vehicle or machinery.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) 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.

Glimepiride is a sulfonylurea anti-diabetic agent which decreases blood glucose concentrations. The primary mechanism of action of glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion in the rhythm of meals. In addition, extrapancreatic effects (e.g. reduction of basal hepatic glucose production and increased peripheral tissue sensitivity to insulin and glucose uptake) may also play a limited role in the activity of glimepiride.

In non-fasting diabetic patients, the hypoglycaemic action of a single dose of glimepiride persist for 24 hours.

Evidence from in vitro and animal studies suggests that there is lower glucagon secretion with glimepiride than glibenclamide and this may give rise to a prolonged reduction of blood glucose levels without increased plasma insulin levels. The clinical significance of these findings is yet to be clarified. A long-term, randomized, placebo-controlled clinical trial demonstrated that Amaryl therapy improves postprandial insulin/C-peptide responses and overall glycaemic control without producing glycaemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels.

The efficacy of Amaryl is not affected by age, gender or weight. Amaryl therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profile in patients. The physiological response to acute exercise (i.e. reduction of insulin secretion) is still present during glimepiride therapy.