Amaryl 1mg Tablets - (eMC) Print Friendly PDF
Amaryl 1mg Tablets - (eMC) Print Friendly PDF
Amaryl 1mg Tablets - (eMC) Print Friendly PDF
3. Pharmaceutical form
Tablet
The tablets are pink, oblong and scored on both sides.
The tablet can be divided into equal doses.
4. Clinical particulars
4.1 Therapeutic indications
Amaryl is indicated for the treatment of type 2 diabetes mellitus, when diet, physical exercise and weight reduction
alone are not adequate.
4.2 Posology and method of administration
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
Dose 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 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 to 2 weeks between each step, to 2, 3 or 4 mg glimepiride per day.
A dose 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 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 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,
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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 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 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
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.
4.3 Contraindications
Glimepiride 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 change over to insulin
is required.
4.4 Special warnings and precautions for use
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 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
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- 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 doses) 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 bloodglucose-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 gastro-intestinal 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.
4.6 Pregnancy and lactation
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 (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
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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.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
The following adverse reactions from clinical investigations were based on experience with Amaryl 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/l 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 dose (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
Not know: hepatic enzymes increased.
Very rare: hepatic function abnormal (e.g. 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: blood sodium decrease.
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5. Pharmacological properties
5.1 Pharmacodynamic properties
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 sulfonylurea group. It may be used in noninsulin dependent 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 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 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, 6bisphosphate, which in its turn inhibits the gluconeogenesis.
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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 dose 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 dose 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.
5.2 Pharmacokinetic properties
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 approx. 2.5
hours after oral intake (mean 0.3 g/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
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6. Pharmaceutical particulars
6.1 List of excipients
Lactose monohydrate
sodium starch glycollate (type A)
magnesium stearate
microcrystalline cellulose
povidone 25000
red iron oxide (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/Aluminium blisters.
14, 15 (Amaryl 1mg only), 20, 28, 30, 50, 60, 90, 112, 120, 280 and 300 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements
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Legal category
POM
Telephone
+44 (0)1483 505 515
Fax
+44 (0) 1483 554831
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