Amaglime is indicated for the treatment of type 2 diabetes mellitus, when diet,
physical exercise and weight reduction alone are not adequate.

For oral administration.
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.
Posology
The dosage is determined by the results of blood and urinary glucose determinations.
The starting dose is 1 mg glimepiride per day. If good control is achieved, this dosage
should be used for maintenance therapy.
For the different dosage regimens appropriate strengths are available.
If control is unsatisfactory, the dosage should be increased, based on the glycaemic
control, in a stepwise manner with an interval of about 1 to 2 weeks between each
step, to 2, 3, or 4 mg glimepiride per day.
A dosage of more than 4 mg glimepiride per day gives better results only in
exceptional cases.
The maximum recommended dose is 6 mg glimepiride per 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 glimepiride,
concomitant insulin therapy can be initiated if necessary. While maintaining the
glimepiride dose, insulin treatment is started at a 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 first 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 1 mg glimepiride 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 dosage 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 glimepiride
A switch over from other oral hypoglycaemic agents to glimepiride can generally be
done. For the switch over to glimepiride the strength and the half-life of the previous
medicinal product has to be taken into account. In some cases, especially in
antidiabetics with a long half-life (e.g. 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.
The recommended starting dose is 1 mg glimepiride per day. Based on the response
the glimepiride dosage may be increased stepwise, as indicated earlier.
Switch over from insulin to glimepiride
In exceptional cases, where type 2 diabetic patients are regulated on insulin, a
changeover to glimepiride may be indicated. The changeover should be undertaken
under close medical supervision.
Special Populations
Patients with renal or hepatic impairment See section 4.3.
Paediatric population
There are no data available on the use of glimepiride in patients under 8 years of
age. For children aged 8 to 17 years, there are limited data on glimepiride as
monotherapy (see sections 5.1 and 5.2).
The available data on safety and efficacy are insufficient in the paediatric population
and therefore such use is not recommended.
Method of administration
Tablets should be swallowed without chewing with some liquid.

Amaglime is contraindicated in patients with the following conditions: - hypersensitivity to glimepiride, other sulfonylureas or sulfonamides or to any of the excipients listed in section 6.1. - 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.

Amaglime 2 mg tablet must be taken shortly before or during a meal.
When meals are taken at irregular hours or skipped altogether, treatment with
”Glimepiride Tablets” 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 selfcontrol,
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
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
- overdosage with Glimepiride Tablets
- 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 medicinal products (see section 4.5)
Treatment with glimepiride tablets requires regular monitoring of glucose levels in
blood and urine. In addition determination of the proportion of glycosylated
haemoglobin is recommended.

Regular hepatic and haematological monitoring (especially leucocytes and
thrombocytes) are required during treatment with glimepiride tablets
In stress-situations (e.g. accidents, acute operations, infections with fever etc) a
temporary switch to insulin may be indicated.
No experience has been gained concerning the use of glimepiride tablets 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 G6PD-deficiency with sulfonylurea agents can lead to
hemolytic 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 Tablets contains lactose monohydrate. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.

If Amaglime 2 mg 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 doctor.
Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is
known to be influenced by concomitant administration of CYP2C9 inducers (e.g.
rifampicin) or inhibitors (e.g. fluconazole).
Results from an in-vivo interaction study reported in literature show that glimepiride
AUC is increased approximately 2-fold by fluconazole, one of the most potent
CYP2C9 inhibitors.
Based on the experience with glimepiride and with other sulfonylureas, the following
interactions have to be mentioned.
Potentiation of the blood-glucose-lowering effect and, thus in some instances
hypoglycaemia may occur when one of the following medicinal products is taken, for
example:
- phenylbutazone, azapropazone and oxyfenbutazone,
- insulin and oral antidiabetic products, such as 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,
- ACE inhibitors,
- fluoxetine, MAO-inhibitors,
- 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 glucose levels
may occur when one of the following medicinal products is taken for example:
- oestrogens and progestogens
- saluretics, thiazide diuretics
- thyroid stimulating agents, glucocorticoids
- phenothiazine derivatives, chlorpromazine
- adrenaline and sympathicomimetics
- nicotinic acid (high dosages) and nicotinic acid derivatives
- laxatives (long term use)
- phenytoin, diazoxide
- glucagon, barbiturates and rifampicin
- acetazolamide
H2 antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation
or weakening of the blood-glucose-lowering effect.
Under the influence of sympatholytic medicinal products such as beta-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 4
hours before colesevelam. Therefore, glimepiride should be administered at least 4
hours prior to colesevelam.

Pregnancy Category C
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 (see section 5.3).
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.
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.

No studies on the effects on the ability to drive and use machines have been
performed.
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 visual impairment.
This may constitute a risk in situations where these abilities are of special importance
(e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving.
This is particularly important in those who have reduced or absent awareness of the
warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It
should be considered whether it is advisable to drive or operate machinery in these
circumstances.

The following adverse reactions from clinical investigations were based on
experience with glimepiride and other sulfonylureas, were 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).

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 less than 10,000/μl 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.
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 such as dietary habits and dosage
(see further under section 4.4).
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.
Hepato-biliary disorders
Very rare: hepatic function abnormal (e.g. with cholestasis and jaundice), hepatitis
and hepatic failure.
Not known: hepatic enzymes increased.
Skin and subcutaneous tissue disorders
Not known: hypersensitivity reactions of the skin may occur as pruritus, rash, urticaria
and photosensitivity.
Investigations
Very rare: blood sodium decrease.

Symptoms
After ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72
hours, and may recur after an initial recovery. Symptoms may not be present for up to
24 hours 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) overdosage
hospitalisation in an intensive care department is indicated. Start the administration of
glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of
a 50% solution, 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 glimepiride 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.

Pharmacotherapeutic group : Blood glucose lowering drugs, excl. insulins: Sulfonamides, urea
derivatives
ATC Code : A10B B12
Glimepiride is an orally active hypoglycaemic substance belonging to the
sulphonylurea group. It may be used in non-insulin dependent (type 2) diabetes
mellitus.
Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells. As
with other sulfonylureas this effect is based on an increase of responsiveness of the
pancreatic beta 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 ATP-sensitive potassium
channel in the beta cell membrane. Closing the potassium channel induces
depolarisation of the beta 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 beta cell membrane protein which is
associated with the ATP-sensitive potassium channel but which is different from the
usual sulfonylureas 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, 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 minutes or immediately before a meal. In diabetic patients,
good metabolic control over 24 hours 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
Combination therapy with metformin
Improved metabolic control for concomitant glimepiride therapy compared to
metformin alone in patients not adequately controlled with the maximum daily dosage
of metformin has been shown in one 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 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.
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 of age) with type 2 diabetes.
Both glimepiride and metformin exhibited a significant decrease from baseline in
HbA1c (glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.40)). 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.

Absorption
The bioavailability of glimepiride after oral administration is complete. Food intake
has no relevant influence on absorption, only the absorption rate is slightly
diminished. Maximum serum concentrations (Cmax) are reached approx 2.5 hours
after oral intake (mean 0.3 μg/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).
Distribution
Glimepiride has a very low distribution volume (approx. 8.8 litres), which is roughly
equal to the albumin distribution space, high protein binding (>99%) and a low
clearance (approx. 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, which is of relevance for the serum concentrations
under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer
half-lives were noted.

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was
recovered in the urine, and 35% in the faeces. 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 faeces: 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.
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 accumulation.
Special populations
Pharmacokinetics were similar in males and females, as well as in young and elderly
(above 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 resulting from a more rapid elimination because of lower
protein binding.
Renal elimination of the two metabolites was impaired. Overall no additional risk of
accumulation is to be assumed in such patients.
Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to
those in healthy persons.
Paediatric population
A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg
single dose of glimepiride in 30 paediatric patients (4 children aged 10-12 years and
26 children aged 12-17 years) with type 2 diabetes showed mean AUC(0-last) , Cmax
and t1/2 similar to that previously observed in adults.

Preclinical effects observed occurred at exposures sufficiently in excess of the
maximum human exposure as to indicate little relevance to clinical use, or were due
to the pharmacodynamic action (hypoglycaemia) of the compound. This finding is
based on conventional safety pharmacology, repeated dose toxicity, genotoxicity,
carcinogenicity, and reproduction toxicity studies. In the latter (covering
embryotoxicity, teratogenicity and developmental toxicity), adverse effects observed
were considered to be secondary to the hypoglycaemic effects induced by the
compound in dams and in offspring.

Lactose Monohydrate
Povidone K 30
Sodium Starch Glycolate
FD and C Blue 2 Lake high(21DB2806)
Yellow iron Oxide
Magnesium Stearate
Microcrystalline Cellulose

Not Applicable.

The shelf life is 2 years.

Store below 30°C.

-The immediate packaging material is PVC/PVDC/ALU blisters.
-Pack size: TWO (30 & 60 tablets)

Any unused product or waste should be disposed of in accordance with local
requirements.