Antidiabetic , Drugs , Endocrine System / October 12, 2016

Class: Antidiabetic
Dosage Form: Tablets
Description: Sulfonylurea hypoglycemic
Stock: Available
Manufacturer: Sanofi Aventis


Active Ingredient
Glimepiride……………………..1, 2, 3, or 4 mg
Amaryl 1 mg: Lactose, sodium starch glycolate, polyvidone 25000, microcrystalline cellulose, magnesium stearate and iron oxide red (E172)
Amaryl 2 mg: Lactose, sodium starch glycolate, polyvidone, microcrystalline cellulose, magnesium stearate, iron oxide yellow (E172) and indigo camine aluminium lak (E132)
Amaryl 3 mg: Lactose, sodium starch glycolate, polyvidone, microcrystalline cellulose, magnesium stearate and iron oxide yellow (E173)
Amaryl 4 mg: Lactose, sodium starch glycolate, polyvidone, microcrystalline cellulose, magnesium stearate and indigo camine aluminium lak (E132)


Mode of Action
Both in healthy and in patients with type 2 diabetes mellitus, glimperide decreases blood glucose concentrations, mainly by stimulating insulin release from pancreatic beta cells. This effect is based predominantly on an improved responsiveness of the pancreatic beta cells to the physiological glucose stimulus. While achieving an equivalent reduction in blood glucose, the administration of low doses of glimepride to animals and healthy volunteers causes the release of smaller amounts of insulin compared with glibenclamide. This fact points to the existence of extrapancreatic (insulin-sensitizing and insulin-mimetic) effects of glimperide. Moreover, compared to other sulfonylureas, glimepride has less effect on the cardiovascular system. It reduces platelet aggregation (animal and in vitro data) and leads to a marked reduction in the formation of atherosclerotic plaques (animal data).
Insulin release: Like all sulfonylurea, glimepride regulates insulin secretion by interacting with the ATP-sensitive potassium channel in the beta cell membrane. Unlike other sulfonylureas, glimepride binds specifically to a 65 KDA protein located in the membrane of the beta cell. This interaction of glimepride with its binding protein determines the probability of the ATP-sensitive potassium channel being open or close. Glimepride closes the potassium channel. This induces depolarization of the beta cell and results in opening of voltage-sensitive calcium channels and influx of calcium into the cell. Finally, the rise in intra-cellular calcium concentration activates the release insulin through exocytosis. Glimepride associate with and dissociate from its binding protein much more rapidly and hence, frequently than glibenclamide. It is assumed that this characteristic high exchange rate of glimepride with the binding protein is responsible for its pronounced glucose sensitizing effect and for protecting the beta cells from desensitization and premature exhaustion.
Insulin-sensitizing effect: Glimepride augments the normal action of insulin on peripheral glucose uptake.
Insulin-mimetic effect: Glimepride mimics the action of insulin on peripheral glucose uptake and hepatic glucose output. Peripheral glucose uptake occurs by transport into the muscle and fat cells. Glimepride directly increases the number of glucose transport molecules in the plasma membranes of muscle and fat cells. The increased influx of glucose causes an activation of the glycosylphosphatidylinositol specific phospholipase C; as a result, cellular cAMP levels decrease, causing a reduction in activity of protein kinase A; this in turn results in a stimulation of the metabolism of the glucose. Glimepride inhibits hepatic glucose output by increasing the concentration of fructose-2.6-bisphosphate which inhibits gluconeogenesis.
Effects on platelet aggregation and formation of atherosclerotic plaques: Glimepride reduces platelet aggregation in vitro and in vivo. This effect is probably the result of a selective inhibition of cyclooxygenase which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor. Glimepiride significantly reduces the formation of atherosclerotic plaques in animals. The underlying mechanism has still to be elucidated.
Cardiovascular effects: Through ATP-sensitive potassium channels (see above) sulfonylureas also affect the cardiovascular system. Compared with conventional sulfonylureas, glimepiride, has significantly less effect on the cardiovascular system (animal data). This may be explained by the specific nature of its interaction with the binding protein of the ATP-sensitive potassium channel.
Pharmacodynamic Characteristics
In healthy persons, the minimum effective oral dose is approx. 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, i.e. reduction of insulin secretion, is still present under glimepiride. There was no significant difference in effect regardless of whether the drug was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with one single dose. Moreover, in a clinical study, good metabolic control was even achieved in 12 out of 16 patients with renal insufficiency (creatinine clearance 4 to 79 ml/min). Although 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 metformin: In patients not adequately controlled with the maximum dosage of either glimepiride or metformin, combination therapy with both oral antidiabetic agents can be initiated. The improvement in metabolic control in conjunction with combination treatment as compared to treatment with either medicinal product alone has been verified in two studies.
Combination therapy with insulin: In patients not adequately controlled with the maximum dosage of glimepiride, concomitant 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.

The absolute bioavailability of glimepiride is complete. Food intake has no relevant influence on absorption. Maximum serum concentration (Cmax) are reached approx. 2.5 hours after oral intake. (309 ng/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). Glimepiride has a very
low distribution volume (approx. 9.8 liters) which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min). Mean domination serum half-life, which is of relevance for the serum concentration under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted. After a single dose of radio labeled glimepiride, 58% of the radioactivity was recovered in the urine and 35% in the feces. 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 feces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride the terminal half-life 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 cummulation. Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In a single-dose, open-label study conducted in 15 patients with renal impairment, glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (ClCr); (Group I, ClCr 77.7 mI/min, n=5), (Group II, ClCr = 27.4 mI/min, n=3) and (Group Ill, ClCr 9.4 mI/min, n=7). Glimepiride was found to be well tolerated in all 3 groups. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentration to decrease, most probably resulting from a more rapid elimination because of lower protein binding. Renal elimination of the two metabolites was impaired. Results from a multiple-dose titration study conducted in 16 NIDDM patients with renal impairment using doses ranging from 1-8 mg daily for 3 months were consistent with the results observed after a single dose. All patients with a ClCr less than 22 mI/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. Overall, no additional risk of cumulation is to be assumed in such patients. It is not known if glimepiride is dialyzable.
Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.
In animals, glimepiride is excreted into milk.


Amaryl is indicated:

  • In non-insulin-dependent (type 2) diabetes mellitus, whenever blood glucose levels can not be controlled adequately by diet, physical exercise and weight reduction alone. Amaryl may be combined with other, non-betacytotropic oral antidiabetics. Amaryl may also be used together with insulin.
  • Amaryl is not suitable for treatment of insulin-dependent (type 1) diabetes mellitus (e.g. for treatment of diabetics with history of ketoacidosis), of diabetic ketoacidosis or of diabetic precoma or coma.


Amaryl must not be used:

  • In patients hypersensitive to glimepiride, other sulfonylurease, other sulfonamides, or any of the excipients of Amaryl
  • In pregnant and lactating women

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 hepatic function, change-over to insulin indicated, not least to achieve optimal metabolic control.

Drug Interactions:

1. Food:
No information currently deemed necessary.

2. Drug interactions:
Not recommended associations.
No information currently deemed necessary.

3. Take into account:
Based on experience with Amaryl and on what is known of other sulfonylureas the following interactions must be considered:
Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is co-administered with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of CYP 2C9.
Potentiation of the blood glucose lowering effect and, thus, in some instances hypoglycemia may occur when one of the following drugs is taken, for example: insulin and other oral antidiabetics; ACE inhibitors; anabolic steroids and male sex hormones; chloramphenicol; couramin derivatives; guanthidine; isofosfamide; MAO inhibitors; miconazole; fluconazole; paraaminosalycilic acid; pentoxifyllin; high dose parentral; phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfinpyrazone; sulfonamides, antibiotics; tetracycline; tritoqualine; trofosfamide.
Weakening of the blood glucose lowering effect and, thus raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other symathomimetic agents; glucagon; laxatives (after protracted use); nicotinic acid (in high doses); estrogens and progestrogens; phenothiazine; phenytoin; rifampicin; thyroid hormones; H2 receptor antagonists, beta-blockers, clonidine and renertiine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycemia may be reduced or absent. Both acute and chronic alcoholic intake may potentiate or weaken the blood glucose lowering action of Amaryl in an unpredictable fashion. The effects of coumarin derivatives may be potentiated or weakened.

Side Effects:

1. Hypoglycemia:
As a result of the blood-glucose-lowering action of Amaryl, hypogylcemia may occur, based on what is known of other sulfonylureas – may also be prolonged. Possible symptoms of hypogylcemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and brudycardia. 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 hypoglycemic attack may resemble that of a stroke. The symptoms nearly always subside when hypoglycemia is corrected.

2. Eyes:
Especially at the start of treatment, there maybe temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens this being dependent on the blood glucose level.

3. Digestive tract:
Occasionally, gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fullness in the epigastrium pain and diarrhea may occur. In rare cases, there may be elevation of liver enzyme levels. Sulfonylureas, including glimepiride, may also in isolated instances cause impairment of liver function (e.g. with cholestasis and jaundice) as well as and hepatitis which may also lead to liver failure. Blood Changes in the blood picture may occur: Rarely, thrombopenia and, in isolated cases, leucopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop.

4. Other adverse effects:
Occasionally, allergic or pseudoallergic creations may occur, e.g. in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnea and a fall in blood pressure, sometimes progressing to shock. In the event of urticaria a physician must therefore be notified immediately. In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

Dosage and Administration:

1. Dosage:
In principle the dosage of Amaryl is governed by the desired blood glucose level. The dosage of glimepiride must be lowered which is sufficient to achieve the desired metabolic control. During treatment with Amaryl, glucose levels in blood and urine must be measured regularly. In addition, it is recommended that regular determinations of the proportion of glycated hemoglobin be carried out. Mistakes, e.g. forgetting to take a dose, must never be corrected by subsequently taking a larger dose. Measures for dealing with such mistakes (in particular forgetting a dose or skipping a meal) or situations where a dose can not be taken at the prescribed time mast be discussed and agreed between physician and patient beforehand.

2. Initial Dose and Dose Titration:

a) Usual initial dose: 1 mg Amaryl once daily.
If necessary, the daily dose can be raised. It is recommended that the increase be guided by regular blood glucose monitoring, and that the dose be increased gradually, i.e. at intervals of one to two weeks and according to the following dose steps: 1 mg – 2mg – 3 mg – 4mg – 6mg -8 mg.

b) Dose range in patients with well controlled diabetes:
Usual daily doses in patients with well-controlled diabetes are 1 to 4 mg Amaryl. Daily doses of more than 6 mg are more effective only in a minority of patients.
c) Distribution of doses:
Timing and distribution of doses are to be decided by the physician, taking into consideration the patient’s current life-style.
Normally a single daily dose of Amaryl is sufficient.
It is recommended that this dose be taken immediately before a substantial breakfast or – if none is taken – immediately before the first main meal. It is very important not to skip meals after the tablets have been taken. As an improvement in control of diabetes is, in itself, associated with higher insulin sensitivity, glimepiride requirements may fall as treatment proceeds.
To avoid hypoglycemia, timely dose reduction or cessation of therapy must therefore be considered.
Correction of dosage must also be considered, whenever:

  • The patient’s weight changes
  • The patient’s life-style changes
  • Other factors arise which cause an increased susceptibility to hypoglycemia or hyperglycemia (see precautions)

d) Duration of treatment:
Treatment with Amaryl is normally a long-term therapy.

e) Changeover from other oral antidiabetics to Amaryl:
There is no exact dosage relationship between Amaryl and other oral antidiabetics. When substituting Amaryl for other oral antidiabetics, it is recommended that the procedure be the same as for initial dosage. Starting with daily doses of 1 mg. This applies even in cases where the patient is being switched from maximum dose of another oral antidiabetic. Consideration must be given to the potency and duration of action of the previous antidiabetic agent. A break from medication way be required to avoid any summation of effects entailing a risk of hypoglycemia.

f) Use with metformin:
In patients not adequately controlled with maximum daily dose of either glimepiride or metformin, combination therapy with both oral antidiabetic agents may be initiated. As the established therapy with either glimepiride or metformin progresses at the same dose level, the additional metformin or glimepiride treatment is started with low dose, which is then titrated up depending on the desired level of metabolic control up to the maximum daily dose. The combination therapy should be with insulin.
In patients not adequately controlled with the maximum daily dose of Amaryl, concomitant insulin therapy can be initiated. 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.

g) Renal insufficiency:
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 (See pharmacokinetics).

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


Note the following:

  • Certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycemia (as for example in certain disorders of the thyroid function and in anterior pituitary or corticoadrenal insufficiency)
  • Concurrent administration of certain other medicines (see interactions)
  • Treatment with Amaryl in the absence of any indications

If such risk factors for hypoglycemia 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 hypoglycemia which reflect the body’s adrenergic counter regulations (see adverse reactions) may be milder or absent where hypogylcemia develops gradually, in the elderly, and where there is autonomic neruopathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine, or other sympatholytic drugs. Hypogylcemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar).
It is known from other sulfonylurease that, despite initially successfully countermeasures, hypoglycemia may recur. Patients must therefore remain under close observation. Severe hypogylcemia further requires immediate treatment and follow-up by a physician and in some circumstances, in patient hospital care.

Signs and Symptoms
Acute overdosage, as well as, long-term treatment with too high dose of glimepride may lead to severe life-threatening hypoglycemia.

As soon as an overdose of Amaryl has been discovered, a physician must be notified without delay. The patient must immediately take sugar, if possible in the form of glucose, unless a physician is already responsible for the treating the overdose, careful monitoring is essential until the physician is confident that the patient is out of danger. It must be remembered that hypoglycemia may recur after initial recovery. Admission to the hospital may sometimes be necessary even as a precautionary measure. In particular, significant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital.
If, for example, the patient is unconscious, an IV injection of concentrated glucose solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively in adults, administration of glucagon, e.g. in doses of 0.5 to 1 mg IV, SC, or IM, may be considered.
In particular when treating hypoglycemia due to accidental intake of Amaryl in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of Amaryl require detoxification (e.g. by gastric lavage and medicinal charcoal). After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycemia is monitored for at least 24 hours.

Pregnancy and Lactation:

Amaryl must not be given during pregnancy. Otherwise there is a risk of harm to the child. The patient must change over to insulin during pregnancy. Patients planning a pregnancy must inform their physician.

To prevent possible ingestion with the breast milk and possible harm to the child, Amaryl, must not be taken by breast-feeding women. In necessary the patient change over to insulin, or must stop breast-feeding.


The following should be cautioned against:

  • In exceptional stress situations (e.g. trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control
  • In the initial weeks of treatment, the risk of hypoglycemia may be increased and necessitates especially careful monitoring
  • Factors favoring hypoglycemia, include:
    • Unwillingness or (more commonly in older patients) incapacity of the patient to cooperate
    • Undernourishment, irregular mealtimes 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
  • Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after altering treatment or when Amaryl is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.


Chronic toxicity: In subchronic and chronic toxicity studies in rats, mice and dogs, a decline in serum glucose as well as a degranulation of the beta cells.


Pack of 3 strips of 10 tablets each.


Store at room temperature, below 25°C.

No Comments

Leave a Reply

%d bloggers like this:
Skip to toolbar