For the management of patients with type 2 diabetes mellitus when diet, exercise and single agent (glimepiride
or metformin alone) do not result in adequate glycaemic control.

In principle, the dosage of Amaglime-Met is governed by the desired blood glucose level. The dosage of
Amaglime-Met must be the lowest which is sufficient to achieve the desired metabolic control. During treatment
with Amaglime-Met 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
cannot be taken at the prescribed time must be discussed and agreed between physician and patient
beforehand.
As an improvement in control of diabetes is, in itself, associated with higher insulin sensitivity, glimepiride
requirements may fall as treatment proceeds. To avoid hypoglycaemia timely dose reduction or cessation of
Amaglime-Met therapy must therefore be considered. Amaglime-Met is to be administered once per day during
breakfast or the first main meal. The highest recommended dose per day should be 8mg of glimepiride and
2000mg of metformin.
Daily doses of glimepiride of more than 6mg are more effective only in a minority of patients. In order to avoid
hypoglycaemia, the starting dose of Amaglime-Met should not exceed the daily doses of glimepiride or
metformin already being taken.
When switching from combination therapy of glimepiride plus metformin as separate tablets, Amaglime-Met
should be administered on the basis of dosage currently being taken.
Titration:
The daily dose should be titrated based on the glycaemic control, in increments of 1 tablet only, corresponding
to the lowest strength.
Duration of therapy:
Treatment with Amaglime-Met is normally a long-term therapy.
Special Populations:
Children
Data are insufficient to recommend paediatric use of Amaglime-Met.

Renal impairment
A GFR should be assessed before initiation of treatment with metformin containing products and at least
annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly,
renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of
metformin should preferably be divided into 2-3 daily doses.
Factors that may increase the risk of lactic acidosis (see Section Warnings) should be reviewed before
considering initiation of metformin in patients with GFR<60 mL/min.
If no adequate strength of Amaglime-Met is available, individual mono-components should be
used instead of the fixed dose combination.

Amaglime-Met must be swallowed whole and not crushed 

 

For Glimepiride:  in patients hypersensitive to glimepiride, other sulfonylureas, other sulphonamides, or any of the excipients of Amaglime-Met  in pregnant women.  in breast-feeding women. No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function and in dialysis patients. In patients with severe impairment of hepatic function, change-over to insulin is indicated, not least to achieve optimal metabolic control. For Metformin:  Hypersensitivity to metformin or any of the excipients.  Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis, diabetic precoma).  Severe renal failure (GFR˂30ml/min)  Acute conditions with the potential to alter renal function such as: ‐ Dehydration ‐ Severe infection ‐ Shock ‐ Intravascular administration of iodinated contrast agents (see Precautions)  Acute or chronic disease which may cause tissue hypoxia such as: ‐ Cardiac or respiratory failure ‐ Recent myocardial infarction ‐ Shock -Hepatic insufficiency ‐ Acute alcohol intoxication ‐ Alcoholism ‐ Lactation

For Glimepiride:
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.
For Metformin:
 Lactic acidosis
Metformin accumulation occurs at acute worsening of renal function and increases the risk of
lactic acidosis.
In case of dehydration (severe diarrhea or vomiting, fever or reduced fluid intake), metformin should be
temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs)
should be initiated with caution in metformin-treated patients. Other risk factors associated to lactic acidosis are
excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting,
and any conditions associated with hypoxia as well as concomitant use of medicinal products that may cause
lactic acidosis (see Section Contraindications and Section Interactions).
Diagnosis:
Patients and/or caregivers should be informed of the risk of lactic acidosis. In case of suspected symptoms, the
patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are
decreased blood pH, (˂7.35), increased plasma lactate levels (˃ 5 mmol/L), and an increased anion gap and
lactate/pyruvate ratio.
Renal function:
GFR should be assessed before treatment initiation and regularly thereafter (see Section Dosage and
Administration).
Metformin is contraindicated in patients with GFR<30 ml/min and should be temporarily discontinued in the
presence of conditions that alter renal function, (see Section Contraindications).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised
in situations where renal function may become impaired, for example when initiating antihypertensive therapy
or diuretic therapy and when starting therapy with an NSAID.
Administration of iodinated contrast agent:
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in
metformin accumulation and an increased risk of lactic acidosis.
Metformin should be discontinued prior to, or at the time of the imaging procedure and not restarted until 48
hours after, provided that renal function has been re-evaluated and found to be stable (see Section Dosage
and Administration and Section Interactions).

Surgery:
Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy
may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that
renal function has been re-evaluated and found to be stable.
PRECAUTIONS
For Glimepiride:
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.
 overdosage with glimepiride.
 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 corticoadrenal insufficiency).
 concurrent administration of certain other medicines (see Interactions).
 treatment with glimepiride in the absence of any indication.
If such risk factors for hypoglycemia are present, it may be necessary to adjust the dosage of glimepiride 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 regulation (see Adverse
Reactions) may be milder or absent where hypoglycemia develops gradually, in the elderly, and where there is
autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine,
reserpine, guanethidine or other sympatholytic drugs.
Hypoglycemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or
sugar). It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycemia
may recur. Patients must, therefore, remain under close observation. Severe hypoglycemia further requires
immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care.
Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anemia. Since
glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PDdeficiency
and a non-sulfonylurea alternative should be considered.

For Metformin:
Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with
hypothyroidism (see Adverse reactions)
Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which
may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended (see Adverse reactions)

Other precautions:
 All patients should continue their diet with a regular distribution of carbohydrate intake during the day.
Overweight patients should continue their energy-restricted diet.
 The usual laboratory tests for diabetes monitoring should be performed regularly.
 Metformin alone never causes hypoglycemia, although caution is advised when it is used in
combination with insulin or sulfonylureas.

For Glimepiride:
Based on experience with glimepiride 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 CYP2C9.
Potentiation of the blood-glucose-lowering effect and, thus, in some instance’s 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; coumarin derivatives;
cyclophosphamide; disopyramide; fenfluramine; fenyramidol; fibrates; fluoxetine; guanethidine; ifosfamide;
MAO inhibitors; miconazole; fluconazole; paraaminosalicylic acid; pentoxifylline (high dose parenteral);
phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfinpyrazone;
clarithromycin; sulfonamide antibiotics; tetracyclines; 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 sympathomimetic agents; glucagon; laxatives (after protracted use);
nicotinic acid (in high doses); estrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid
hormones.
H2 receptor antagonists, beta-blockers, clonidine and reserpine 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 alcohol intake may potentiate or weaken the blood glucose-lowering action of
glimepiride in an unpredictable fashion. The effect of coumarin derivatives may be potentiated or weakened.
Bile acid sequestrant: 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.
For Metformin:
Concomitant use not recommended:
Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting
or malnutrition or hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medications.
Iodinated contrast agents
Metformin must be discontinued prior to, or at the time of the image procedure and not restarted
until at least 48 hours after, provided that renal function has been re-evaluated and found to be
stable (See Section Dosage and Administration and Warnings).

Combinations requiring precautions for use:
Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g.
NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor
antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with
metformin, close monitoring of renal function is necessary.
Glucocorticoids (systemic and local routes), beta-2-agonists and diuretics have intrinsic hyperglycemic activity.
Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of
treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon
its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of
the antidiabetic drug during therapy with the other drug and upon its discontinuation.
Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, a close monitoring of the INR
is recommended.
Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels are
recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin
must be adjusted if necessary.
Organic cation transporters (OCT)
Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with
• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole)
may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma
concentration.
• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of
metformin.
Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered
with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of
metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

 

Pregnancy
For Glimepiride:
Glimepiride must not be taken during pregnancy. Otherwise there is risk of harm to the child. The patient must
change over to insulin during pregnancy.
Patients planning a pregnancy must inform their physician. It is recommended that such patients change over
to insulin.
For Metformin:
To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with
respect to pregnancy, embryonal or fatal development, parturition or postnatal development.
When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with
metformin, but insulin should be used to maintain blood glucose levels as close to normal as possible in order
to lower the risk of fatal malformations associated with abnormal blood glucose levels.
Lactation
For Glimepiride:
To prevent possible ingestion with the breast milk and possible harm to the child, glimepiride must not be taken
by breast-feeding women. If necessary, the patient must change over to insulin, or must stop breast-feeding.

For Metformin:
Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should
be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the
compound to the mother.

For Glimepiride:
Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after
altering treatment or when glimepiride is not taken regularly. This may, for example affect the ability to drive or
to operate machinery.
For Metformin:
Metformin monotherapy does not cause hypoglycemia and therefore has no effect on the ability to drive or to
use machines.
However, patients should be alerted to the risk of hypoglycemia when metformin is used in combination with
other antidiabetic agents (sulfonylureas, insulin, repaglinide).

The following CIOMS frequency rating is used, when applicable:
Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very
rare<0.01%, Unknown (cannot be estimated from available data).
For Glimepiride and Metformin
The use of a combination of both compounds, either as a free combination or as a fixed combination, is
associated with the same safety characteristics as the use of each compound separately.
For Glimepiride:
 Metabolism and nutrition disorders
As a result of the blood-glucose-lowering action of glimepiride, hypoglycemia may occur, which may also be
prolonged.
Possible symptoms of hypoglycemia 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 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 hypoglycemic attack may resemble that of a stroke.

The symptoms nearly always subside when hypoglycemia is corrected.
 Eye disorders
Especially at the start of treatment, there may be 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 blood glucose level.
 Gastrointestinal disorders
Occasionally, gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fulness in the
epigastrium, abdominal pain and diarrhea may occur.
In isolated cases, there may be hepatitis, elevation of liver enzyme levels and/or cholestasis and jaundice,
which may progress to life-threatening liver failure but can regress after withdrawal of glimepiride.
Dysgeusia (frequency not known)
 Blood and lymphatic system disorders
Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia,
hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Cases of
severe thrombocytopenia with platelet count less than 10,000/μl and thrombocytopenic purpura have been
reported in post-marketing experience (frequency not known).
 Skin and subcutaneous tissue disorders
Alopecia (frequency not known)
 General disorders
Occasionally, allergic or pseudo-allergic reactions 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.
 Investigations
Glimepiride, like all sulfonylureas, can cause weight gain (frequency not known).

For Metformin:
Gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite (>10%) are
very common: these occur most frequently during initiation of therapy and resolve spontaneously in most
cases. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken in 2 or 3 daily
doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

- Metallic taste (3%) is common.
- Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is
regarded as very rare (<0.01%).
- A decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated
long-term with metformin and appears generally to be without clinical significance (<0.01%).
However, cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in postmarketing
experience (frequency not known) (see Precautions)
-Lactic acidosis (0.03 cases/1000 patient-years) is very rare (see Warnings).
- Hemolytic anemia (frequency unknown)
- Reduction of thyrotropin level in patients with hypothyroidism (see Precautions) (frequency unknown)
- Hypomagnesemia in the context of diarrhea (frequency unknown)
- Encephalopathy (frequency unknown)
- Photosensitivity (frequency unknown)

-Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving upon metformin
discontinuation

Reporting of suspected adverse reactions
To reports any side effect(s):
‐ Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966‐11‐205‐7662
o SFDA call center: 19999
o Toll free phone: 8002490000
o E‐mail: npc.drug@sfda.gov.sa
o Website: https://ade.sfda.gov.sa

Other GCC States:
‐ Please contact the relevant competent authority

For Glimepiride:
Signs and Symptoms:
Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe lifethreatening
hypoglycemia.

Management:
As soon as an overdose of glimepiride 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 has already
undertaken responsibility for 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 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 intravenous 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 i.v., s.c. or i.m. may be considered.
In particular when treating hypoglycemia due to accidental intake of glimepiride 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 glimepiride 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 does not recur.
The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a
protracted course, Hypoglycemia, or the danger of slipping back into hypoglycemia, may persist for several
days.
For Metformin:
hypoglycemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in
such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic
acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate
and metformin is hemodialysis.
Pancreatitis may occur in the context of a metformin overdose.

Amaglime-Met is a combined hypoglycemic medicine, which is composed of glimepiride
and metformin.
Pharmacodynamics of glimepiride
Glimepiride, one of the active substances of Amaglime-Met, is an oral hypoglycemic medicine -
sulfonylureas of the III generation.
Glimepiride stimulates secretion and release of insulin from the pancreas beta-cells (pancreatic
effect), improves sensitivity of peripheral tissues (muscle and fat) to the action of endogenous
insulin (extrapancreatic action).

Effect on insulin secretion
Sulfonylureas increase insulin secretion by closing the ATP-dependent potassium channels, located in the
cytoplasmic membrane of pancreatic beta-cells. By closing the potassium channels, they cause depolarization
of the beta-cells, thus facilitating opening of calcium channels and increasing of transmission of calcium into the
cells. Glimepiride is bounded and unbounded from the protein of pancreatic beta cells at a high replacement
rate of (mol. mass -65 kD/SURX), which is associated with the ATP-dependent potassium channels, however it
is different from the binding sites of conventional sulfonylureas (protein with mol. mass – 140 kD/SUR1).
This process leads to release of insulin by exocytosis, and the amount of secreted insulin is significantly lesser
than with sulfonylureas of II generation (e.g. glibenclamide). Minimum stimulating effect of glimepiride on insulin
secretion is provided and there is a lower risk of development of hypoglycemia.
Extrapancreatic activity
As with traditional sulfonylureas, but to a greater extent, glimepiride has pronounced extrapancreatic effects
(reduction of insulin resistance, antiatherogenic, antiplatelet and antioxidant action).
Utilization of glucose by peripheral tissues (fat and muscle) occurs via specific transporter proteins (GLUT1 and
GLUT4), located in the cell membranes. Transportation of glucose in these tissues in diabetes mellitus type 2 is
limited in rate of glucose utilization stage. Glimepiride very rapidly increases the number and activity of
molecules, glucose transporter (GLUT1 and GLUT4), which leads to an increase in glucose uptake by
peripheral tissues.
Glimepiride has a weak inhibitory effect on ATP-sensitive potassium channels of cardiomyocytes. Upon
administration of glimepiride, the ability of metabolic adaptation to myocardial ischemia is preserved.
Glimepiride increases the activity of phospholipase C, which results reduction of intracellular calcium
concentration in muscle and fat cells, causing decrease in the activity of proteinkinase A, which in turn, leads to
lead to stimulation of glucose metabolism.
Glimepiride inhibits hepatic glucose output by increasing the intracellular concentration of fructose-2,6-
bisphosphate, which in turn inhibits gluconeogenesis.
Glimepiride selectively inhibits cyclooxygenase and reduces conversion of arachidonic acid to thromboxane A2,
important endogenous factor for platelet aggregation.
Glimepiride reduces the lipid content, significantly decreases lipid peroxidation and promotes its
anti-atherogenic effect.
Glimepiride increases the content of endogenous Q-tocopherol, activity of catalase, glutathione peroxidase and
superoxide dismutase, thereby reducing the severity of oxidative stress, always presented in the body of the
patient with diabetes mellitus type 2.
Pharmacodynamics of metformin
Metformin is a hypoglycemic medicine from the biguanide group. Its hypoglycemic effect is possible only under
condition of preservation of insulin secretion (although reduced).
Metformin has no effect on the beta-cells of the pancreas and does not increase secretion of insulin. Metformin
at therapeutic doses do not cause hypoglycemia in humans. The mechanism of action of metformin is not yet
completely learnt. It is assumed that metformin may potentiate the effects of insulin or that it can increase the
effects of insulin receptors in peripheral areas.
Metformin increases insulin sensitivity due to increase in the number of insulin receptors on cell surface
membranes. Besides metformin inhibits gluconeogenesis in the liver, reduces formation of free fatty acids and
fat oxidation, reduces the concentration of triglyceride (TG) and low-density lipoproteids (LDL) and very lowdensity
lipoprotein (VLDL) in blood.
Metformin slightly reduces appetite and decreases absorption of carbohydrates in the intestine.
It improves blood fibrinolytic properties due to suppression of tissue plasminogen activator inhibitor.

 

Pharmacokinetics of glimepiride
With multiple daily dose of 4 mg glimepiride, maximum serum concentration (Cmax) is achieved after about 2.5
hours and is 309 ng / ml; there is a linear relationship between dose and Cmax, as well as between the dose
and AUC (area under plasma “concentration – time” curve). When administered, bioavailability of glimepiride is almost complete. Food intake has no significant effect on absorption, with the exception of a slight slow-down
of the rate of absorption.
Glimepiride is characterized by a very low distribution volume (approximately 8.8 liters), approximately equal to
the albumin distribution volume, high plasma protein binding level (99%) and low clearance (about 48 ml/min).
After a single oral administration of glimepiride, 58% of the dose is excreted by the kidneys (as metabolites)
and 35% of the dose is excreted through the intestines. Half-life in case of plasma concentrations of glimepiride
in plasma, corresponding to the multiple administration, is 5-8 hours. After administration of high dose, half-life
increases slightly.
In urine and faeces two inactive metabolites are revealed, resulting the metabolism in the liver, one of them is
hydroxy derivative, and the other - carboxy derivative. After oral administration of glimepiride, terminal half-life
of these metabolites is 3-5 hours and 5-6 hours, respectively.
Glimepiride is excreted in breast milk and crosses the placental barrier. Glimepiride poorly crosses the bloodbrain
barrier.
Comparison of single and multiple (2 times daily) administration of glimepiride did not reveal significant
differences in the pharmacokinetic parameters and their variability between patients was insignificant.
Significant accumulation of glimepiride was absent.
Pharmacokinetic parameters of glimepiride are the same for patients of different genders and various ages.
In patients with impaired renal function (low creatinine clearance) tended to increase clearance of glimepiride
and decrease in its average concentrations in the blood serum, which is likely caused by a more rapid
clearance of glimepiride due to its lower binding to plasma proteins. Thus, there is no additional risk of
accumulation of glimepiride in such categories of patients.
Pharmacokinetics of metformin
Metformin is absorbed from the gastrointestinal tract adequately after oral administration. Absolute
bioavailability is 50-60%. Cmax, composed of average 2 mg/ml, is reached after 2.5 hours. In case of
simultaneous food intake, absorption of metformin is reduced and slowed down.
Metformin is rapidly distributed into the tissue, practically does not bind to plasma proteins. It is metabolized to
a very small extent and excreted by the kidneys. The clearance in healthy subjects is 440 ml/min (4 times
greater than that of creatinine), indicating presence of active tubular secretion of metformin. Half-life of
metformin is approximately 6.5 hours.
There is a risk of metformin accumulation in case of renal insufficiency.
Pharmacokinetics Amaglime-Met with the fixed dose of glimepiride and metformin
In case of administration of fixed dose of the combined drug Amaglime-Met (tablet containing glimepiride 2 mg
+ metformin 500 mg), Cmax and AUC values correspond to bioequivalence criteria when compared to the
same parameters in case of administration of the same combination as separate preparations (tablet of
glimepiride 2 mg and metformin 500 mg).
In addition, dose-proportional increase of Cmax and AUC of glimepiride was shown by increasing
the dose from 1 mg to 2 mg in the combined fixed-dose preparations with a constant dose of
metformin (500 mg) in the composition of these preparations.
No other significant differences are observed in safety, including profile of adverse effects in patients taking
the drug Amaglime-Met 1 mg +500 mg, and the patients taking the drug Amaglime-Met 2 mg +500 mg.

Not applicable.

Tablet core: Microcrystalline Cellulose, Crosspovidone, Sodium Starch Glycolate and Povidone K30,
Magnesium Stearate and Lactose Monohydrate
Tablet coating: Hypromellose, Polyethylene Glycol /Marcogol, Titanium Dioxide and Carnauba Wax.

Not applicable.

2 years.

Store below 30°C.

Clear (PVC/PE/PVdC 90 GSM) - Aluminum blister.
28 film coated tablets, packed in 4 blisters (7 tablets / blister).

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