As an adjunct to diet and exercise in Non-Insulin-Dependent Diabetes Mellitus (NIDDM) – Type 2 patients:

-In case that the monotherapy with glimepiride or metformin do not result in adequate glycemic control

- Replacement of combination therapy of glimepiride and metformin.

This drug should be administered once or twice per day immediately before or with the meals.

The dosage may be individualized based on the patient’s current treatment regimen, efficacy and tolerability; adequate monitoring of blood glucose levels should be performed for this. Generally, it should be recommended to initiate the lowest effective dose and increase the dose depending on the patient’s current medication and blood glucose levels. The initial daily dose of this drug in a clinical study was glimepiride / metformin hydrochloride 2mg/500mg which was gradually increased up to glimepiride / metformin hydrochloride 8 mg/2000 mg as per the blood glucose monitoring results. Although glimepiride monotherapy generally had little additional effects when dosed at 4mg or more a day, some patients showed improved metabolic control when the dose was increased up to 6mg.

When switching from combination therapy, this drug should be administered based on the dosage and administration method of glimepiride and metformin hydrochloride that are being currently administered in combination.

Although the previous dose was omitted, do not overdose this drug for the next dose

 

Geriatric population:

With regard to decreased renal function of geriatric patients, the dosage of metformin HCl should be adjusted based on renal function of patients and regular monitoring of renal function is necessary. Metformin HCl and glimepiride are known to be mostly excreted by the kidney. Because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, it should only be used in patients with normal renal function.

 

 

Pediatric population:

Safety and effectiveness in pediatric patients have not been established. Studies in maturity-onset diabetes of the young (MODY) have not been conducted .

 

<Metformin single agent >

Prior to metformin treatment, it should be confirmed whether the patient has a type 2 diabetes mellitus. Although a one-year controlled clinical trial confirmed that metformin did not affect growth and sexual maturation, no long-term study results are available for these specific points. Therefore, it is recommended that the impact of metformin on these parameters be carefully monitored when this drug is administered to children including those before puberty in particular .

Children aged 10 to 12: Only 15 children aged 10 to 12 participated in a controlled clinical trial in children and adolescents in the growth phase. Although the efficacy and safety of metformin in children aged 12 or below did not differ from those in children aged 12 or above, caution should be exercised when metformin is prescribed to children aged 10 to 12.

1) Patients with Insulin-dependent (type I) diabetes mellitus (e.g., diabetic patients with a history of ketonemia), diabetic ketonemia, diabetic coma or precoma, acute or chronic metabolic acidosis 2) Patients with a history of hypersensitivity to any of the excipients of this drug, or sulfonylureas, sulfonamides, or biguanides 3) There is no experience in patients with severe hepatic dysfunction or hemodialysis. In case of severe hepatic or renal function disorders, a shift to insulin is required to achieve adequate control of blood glucose . 4) Women who is or suspected of being pregnant, nursing mothers 5) Patients susceptible to lactic acidosis, patients with a history of lactic acidosis, renal failure or renal dysfunction (e.g., as suggested by plasma creatinine levels 1.5 mg/dL[males], 1.4 mg/dL[females], or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse(shock), acute myocardial infarction, and septicemia 6) Patients who receive radiologic tests involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography(CT) scans with intravascular contrast materials) (Such tests can lead to acute renal dysfunction and have been associated with lactic acidosis in patients receiving this drug. Therefore, in patients for whom any such test is planned, this drug should be temporarily discontinued 48 hours before the procedure, and reinstituted only after renal function has been re- evaluated and found to be normal.). Besides, patients with acute symptoms with the potential to alter renal function (dehydration, severe infection, shock) should be contraindicated . 7) Severe infections, before and after surgery [This drug should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.], patients with serious trauma 8) Malnourished, starving or debilitated patients or patients with pituitary or adrenal insufficiency 9) Hepatic dysfunction (Since impaired hepatic function has been associated with some cases of lactic acidosis, this drug should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.), pulmonary infarction, severe lung dysfunction, other condition likely to accompany hypoxia (cardiac or respiratory failure, recent myocardial infarction, shock), excessive alcohol intake, dehydration, gastrointestinal disturbance including diarrhea and vomiting 10) Patient with congestive heart failure requiring pharmacologic management and recent myocardial infarction, severe cardiovascular collapse, or respiratory disturbance . 11) As this drug contains lactose, it should not be administered to a patient who has a genetic disease like galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption.

1.1  Warnings

1)  Serious lactic acidosis or hypoglycemia may occur.

2)  Increased risk of cardiovascular mortality

The administration of oral hypoglycemic drug has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP) to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes mellitus.

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5g per day) or phenformin (100 mg/day) had a rate of cardiovascular mortality 2.5 times that of patients treated with diet alone and it resulted in discontinuation of the use of tolbutamide or phenformin. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glimepiride and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) and one drug in the biguanide class (phenformin) are included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

 

Precautions

Careful monitoring is required during the first week of treatment because of increased risk of hypoglycemia. The patients or conditions at risk of hypoglycemia are as follows ;

1)      Unwillingness or incapacity of the patient to cooperate (more common in older patients).

2)      Malnutrition, irregular mealtimes, skipped meals

3)      Imbalance between physical exertion and carbohydrate intake, severe myokinesis

 

4)      Consumption of alcohol

5)      Renal insufficiency (may lead to a more sensitive reaction to the blood glucose lowering effect of glimepiride).

6)      Severe hepatic insufficiency

7)      Overdose with this drug

8)      Certain uncompensated disorders of the endocrine system (e.g., disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency): may affect carbohydrate metabolism or counter-regulation of hypoglycemia

9)      Concurrent administration of certain other medicines (see 4.5. Interactions)

 

If such risk factors of hypoglycemia are present, it may be necessary to adjust the dosage of this drug 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 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 sympatholytic drugs.

1.1  Glimepiride

When other drugs are concomitantly administered to or withdrawn from a patient receiving this drug, both undesired increases and decreases in the hypoglycemic action of glimepiride can occur. Based on experience with this drug and with other sulfonylureas, the following interactions must be considered :

1)      This drug is metabolized by cytochrome P450 2C9 (CYP2C9). This fact should be considered in case of concomitant administration of CYP2C9 inducers (e.g., rifampicin) or inhibitors (e.g., fluconazole).

2)      Drugs potentiating the blood-glucose-lowering effect: Insulin and oral anti diabetic products, Non- Steroidal Anti-Inflammatoray Drugs(NSAIDs), ACE inhibitors, allopurinol, anabolic steroids, male sex hormones, chloramphenicol, coumarin anticoagulants, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, miconazole,fluconazole, para-aminosalicylic acid, pentoxifylline(high dose parenteral), pheylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolone antibiotics, salicylates, sulfinpyrazone, clarithromycin, sulfonamide, tetracyclines, tritoqualine, trofosfamide, sympathetic inhibitor

3)      Drugs weakening the blood-glucose-lowering effect: Acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine (adrenaline) or sympathicomimetics, glucagons, laxatives (long term use), nicotinic acid(high dose), estrogens, progestogens, oral contraceptives, phenothizines, phenytoin, rifampicin, thyroid hormones, chlorpromazine, isoniazid

4)      Drugs potentiating or weakening the blood-glucose-lowering effectH2 antagonists, clonidine, reserpine

 

5)      Beta-blockers reduce glucose tolerance. Reduction of glucose tolerance may change metabolic control in diabetic patients. Beta-blockers may increase the risk of hypoglycemia (due to failure of counter-regulation).

6)      Drugs reducing or blocking the signs of adrenergic counter-regulation to hypoglycemia: Sympatholytic drugs, e.g : Beta-blockers, clonidine, guanethidine, reserpine

7)      Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of this drug in an unpredictable fashion .

8)      This drug may either potentiate or weaken the effects of coumarin derivatives anticoagulant .

9)      Bile acid sequestrant: 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.

 

Metformin

1)      Lactic acidosis may occur by concomitant administration of the following drugs. When these drugs are administered concomitantly, patients should be closely monitored: iodinated contrast materials, antibiotics having strong nephrotoxicity (gentamicin, etc.)

2)      The hypoglycemic action of co-administration with the following drugs may be potentiated or weakened. When these drugs are administered, the blood glucose level and patient should be observed closely .

a.       Drugs potentiating the hypoglycemic action: Insulin, sulfonamides, and sulfonylureas products, meglitinides (repaglinide, etc.), alpha-glycosidase inhibitor(acarbose), anabolic steroids, guanethidine, salicylates(aspirin, etc.), beta-blockers (propranolol, etc), MAO inhibitors, ACE (Angiotensin Converting Enzyme) inhibitors

b.       Drugs weakening the hypoglycemic action: Epinephrine, sympathomimetics, corticosteroids, thyroid hormones, estradiol, estrogens, oral contraceptive, thiazide and other diuretics, pyrazinamide, isoniazid, nicotinic acid, phenothizines, phenytoin, calcium channel blockers, beta-2-agonists(Salbutamol, formoterol, etc.).

3)      Glyburide: In a single-dose interaction study in type 2 diabetes subjects, co-administration of metformin HCl and glyburide did not result on any changes in either pharmacokinetics or pharmacodynamics of metformin HCl. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between metformin HCl blood levels and pharmacodynamic effects makes the clinical significance of this interaction uncertain .

4)      Furosemide: A single-dose, metformin HCl-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co- administration. Furosemide increased the metformin HCl plasma concentration and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin HCl renal clearance. When administered with metformin HCl, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by

 

32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin HCl and furosemide when co-administered chronically .

5)      Nifedipine: A single-dose, metformin HCl-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin HCl Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin HCl. Metformin HCl had minimal effects on nifedipine .

6)      Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin HCl by competing for common renal tubular transport systems. Such interaction between metformin HCl and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple- dose, metformin HCl-cimetidine drug interaction studies, with a 60% increase in peak metformin HCl plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin HCl AUC. There was no change in elimination half-life in the single-dose study. Metformin HCl had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin HCl and/or the interacting drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system .

7)      Other: In healthy volunteers, the pharmacokinetics of metformin HCl and propranolol, and metformin HCl and ibuprofen were not affected when co-administered in single-dose interaction studies. Metformin HCl is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to plasma proteins.

Pregnancy

This drug must not be taken during pregnancy as teratogenecity was reported in animal studies and lactic acidosis is easy to occur to pregnant women. Pregnant patient or the patient planning a pregnancy must inform their physician in order to reduce the risk of fetal congenital anomaly caused by abnormal glycemic levels. It is recommended that such patients change over to insulin to maintain the blood glucose level within a normal range if possible.

 

Lactation

This drug must not be taken by breast-feeding women as glimepiride and metformin were reported to be excreted into milk in lactating rats. If necessary the patient must change over to insulin, or must stop breast-feeding.

 

Patients should be advised to drive a car or operate machinery with caution.

Blood and lymphatic system disorders

Following hematological abnormalities may occur; Rarely, thrombopenia, in isolated cases, leucopenia, or hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis, pancytopenia may develop. Because it is reported that aplastic anemia may occur with other sulfonylureas, careful monitoring should be performed. If these occur, the medication should be discontinued and adequate treatment taken.

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).

 

Metabolism and nutrition disorders Hypoglycemia.

It is known from other sulfonylureas that, despite of initially successful countermeasures, hypoglycemia may recur. Patients must, therefore, remain under close observation by a physician or pharmacist. Possible symptoms of hypoglycemia include headache, ravenous hunger, nausea, vomiting, fatigue, falling asleep, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, loss of self-control, delirium, cerebral convulsions, loss of consciousness, 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. Severe hypoglycemia further requires immediate treatment and follow-up by a physician, in some circumstances, in- patient hospital care. Hypoglycemia can be almost promptly controlled by immediate intake of carbohydrates (glucose or sugar, e.g., lump sugar, fruit juice including sugar, tea including sugar, and etc). Patients should carry approximately at least 20g of sugar for this. The patients and his/her family should be educated about the dangerousness, symptoms, treatment and risk factors of hypoglycemia. Help may be necessary from other's to avoid complications. Artificial sweeteners have no effect in controlling blood glucose.

 

Lactic acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with this drug. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxia .

 

Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5㎍/mL are generally found .

The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patients/year, with approximately 0.015 fatal cases/1000 patients/year). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications .

The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients on this drug and by using the minimum effective dose of this drug. In addition, this drug should be immediately withheld in the presence of any condition associated with hypoxemia, dehydration, or septicemia .

Because impaired hepatic function may significantly limit the ability to clear lactate, this drug should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking this drug, since alcohol potentiates the effects of metformin HCl on lactate metabolism. In addition, this drug should be temporarily discontinued prior to any intravascular radio-contrast test and for any surgical procedure .

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur . Plasma electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful to identify lactic acidosis. Once a patient is stabilized on any dose level of this drug, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease .

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5mmol/L in patients taking this drug do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling .

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketouria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking this drug, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to

 

correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.

 

A decrease of plasma Vitamin B12 level was observed in patients who take metformin for a long time. Plasma folic acid level was not significantly decreased. Only megaloblastic anemia was reported in connection with this drug, but symptoms of neuropathy were not increased. Therefore, proper monitoring of plasma Vitamin B12 or periodic parenteral supplement of Vitamin B12 should be considered.

 

Gastrointestinal disorders

GI symptoms (diarrhea, nausea, vomiting, abdominal distention, anorexia, dyspepsia, constipation, abdominal pain) are the most common reactions to metformin and are approximately 30% more frequent in patients on metformin monotherapy than in placebo-treated patients, particularly during initiation of this drug therapy. These symptoms are generally transient and resolve spontaneously during continued treatment. Occasionally, temporary dose reduction may be useful. In clinical trials, approximately 4% of patients discontinued metformin due to gastrointestinal reactions. Because GI symptoms during therapy initiation appear to be dose-related, they may be decreased by gradual dose escalation and by having patients take this drug with meals. Because significant diarrhea and/or vomiting may cause dehydration and prerenal azotemia, under such circumstances, this drug should be temporarily discontinued. For patients who have been stabilized on this drug, nonspecific GI symptoms should not be attributed to therapy but may be related to concomitant illness or lactic acidosis .

Glimepiride therapy is occasionally associated with GI symptoms such as nausea, vomiting, epigastric bloating or tightness, abdominal pain, and diarrhea

 

Hepato-biliary disorders

In some cases, elevation of liver enzymes and impairment of liver function(e.g., cholestasis and jaundice) may occur, as well as hepatitis which may progress to liver failure.

 

Skin and subcutaneous tissue disorders

Occasionally, allergic or pseudo-allergic reactions (e.g., erythema, itching, urticaria, or rashes) may occur. Most of these reactions are mild but 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. Crossover allergic reactions with sulfonylureas or sulfonamides and their derivatives may occur.

 

In isolated cases, allergic vasculitis, hypersensitivity of skin to light, or a decrease in serum sodium concentration may occur.

 

Laboratory tests:

 

Periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (plasma creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, possibility of vitamin B12 deficiency should be checked.

 

Special senses:

During initiation of metformin therapy, approximately 3% of patients may complain of an unpleasant or metallic taste, which usually resolve spontaneously. Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels.

 

To report any side effect(s):

Saudi Arabia

National Pharmacovigilance & Drug Safety Centre (NPC):

Fax: +966-11-205-7662

Toll free phone: 8002490000 E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

Sanofi - Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Because this drug includes glimepiride, of this drug can produce hypoglycemia .

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 .

Mild hypoglycemia without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger .

Treatment primarily consists of preventing absorption by inducing vomiting and then drinking soft drink or water containing activated charcoal (absorbent) and sodium-sulphate (laxative). In case quite a lot of amount is absorbed, gastric lavage should be conducted and the activated charcoal and sodium-sulphate should be used later .

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 hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated glucose solution (e.g. a rapid intravenous injection of 50% concentrated glucose solution or 40 ml of 20% solution followed by a continuous infusion of a more diluted (10%) glucose solution at a rate that maintain the blood glucose at a level above 100 mg/dL). 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. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery .

 

In particular when treating hypoglycemia from accidental intake of glimepiride in infants and young children, the dose of glucose given should be very carefully adjusted and the blood glucose level should be closely monitored .

Because this drug includes metformin, lactic acidosis may occur. Hypoglycemia has not been seen with metformin HCL doses of up to 85 g. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis is most effective treatment for removal of accumulated drug from patients in whom metformin overdose is suspected .

Pancreatitis may occur in the context of a metformin overdose.

 

1.1  Glimepiride:

Pharmacotherapeutic group: Blood glucose lowering drugs, excl. insulins: Sulfonamides, urea derivatives. ATC Code: A10B B12.

Glimepiride is an orally active hypoglycemic substance belonging to the sulfonylurea group. It may be used in non-insulin 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, 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 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 Pediatric 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 pediatric patients.

 

Metformin:

Pharmacotherapeutic group: Blood glucose lowering drugs. Biguanides; ATC code: A10BA02

 

Mechanism of action

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.

 

Metformin may act via 3 mechanisms:

• reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.

• in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.

• and delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

 

Pharmacodynamic effects

In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.

In humans, independently of its action on glycaemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

 

Clinical efficacy

An open, randomized, multicenter clinical study was conducted to compare the efficacy and safety of fixed combination of glimepiride/metformin versus free combination of sulfonylurea and metformin in Korean subjects with type 2 diabetes mellitus.10 A total of 209 subjects with T2DM were randomized to a pre-defined titration regimen of fixed (n=105) and free (n=104) combination glimepiride and metformin taken twice a day before a meal for 16 weeks.11 Fixed combination tablets were supplied as either glimepiride 1 mg/metformin 250 mg or glimepiride 2 mg/metformin 500 mg.12 Free combinations were supplied as either glimepiride 1 mg or glimepiride 2 mg and metformin 250 mg or metformin 500 mg.

The primary efficacy parameter was the change in HbA1c(%) from baseline to endpoint of each subject. Baseline HbA1c was 7.99% in the fixed combination group and 7.88% in the free combination group. HbA1c decreased by mean 1.13% (adjusted mean reduction 1.09%) in the fixed combination group and mean 1.04% (adjusted mean reduction 1.08%) in the free combination group during the study. The difference in the adjusted mean change between the two groups was -0.01% and corresponding two-sided 95% confidence interval was (-0.21%, 0.19%), which was included in the predefined equivalence interval (-0.5%, +0.5%). The fixed and free combinations were demonstrated as equivalent on efficacy.

Compliance was 94.6% for the fixed combination group versus 91.4% for the free combination group (p=0.1511).

There was no difference in patients with hypoglycemic episodes between the fixed combination group versus the free combination group (45.5% vs. 41.4%, respectively p=0.6838).

 

Pediatric population

Controlled clinical studies in a limited pediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycemic control to that seen in adults.

 

1.1  The Cmax and AUC values of a fixed dose combination product (glimepiride 2 mg and metformin 500 mg tablet) met the bioequivalence criteria when compared with the values of the free combination product of glimepiride 2 mg tablet and metformin 500 mg tablet.

The following supplementary information is provided:

An open label, randomized, 2-period, 2-treatment, 2 sequence single dose crossover study was conducted in 32 healthy Korean subjects (16 males and 16 females) under fasting conditions to evaluate bioequivalence between a fixed dose combination (glimepiride 2 mg and metformin 500 mg tablet) versus the free combination of glimepiride 2 mg tablet and metformin 500 mg tablet. There was a 7-day washout period between each treatment period.

Pharmacokinetic parameters:

	Glimepiride		Metformin
	Free combination	Fixed combination	Free combination	Fixed combination
Tmaxaa	3.0 [1.0 - 5.0]	1.0 [0.5 - 5.0]	2.0 [0.5 – 4.0]	2.5 [0.5 – 4.0]
Cmax	202 ± 51	205 ± 56	1122 ± 291	1084 ± 305
AUC0-8	922 ± 265	903 ± 250	6595 ± 1272	6382 ± 1365
t1/2	6.51 ± 2.03	6.94 ± 2.61	5.10 ± 0.93	5.40 ± 1.13

a Values are presented as mean ± SD except Tmax : median [min – max]

Cmax/D and AUClast/D of glimepiride with AMARYL®M 1/500 mg are equivalent to those observed with AMARYL® M 2/500 mg. The Cmax and AUClast of glimepiride increased proportionately as the dose of glimepiride increased from 1 mg to 2 mg. In addition, no clinically meaningful difference between the test group (AMARYL®M 1/500 mg) and the reference group (AMARYL®M 2/500 mg) was observed from diverse safety evaluations including the adverse event profile.

Pharmacokinetic parameters normalized to dose:

Parameters (normalized to dose)	Test: AMARYL® M 1/500 Glimepiride 1 mg	Reference: AMARYL® M 2/500 Glimepiride 2 mg	Point estimate of Log- transformed Difference (90% Confidence Interval)	Ratio 2) (90% Confidence Interval)
Cmax/Dose	5.07±0.34 1)	4.96±0.33 1)	0.1014	1.11
(μg/L/mg)			(0.0099-0.1930)	(1.01-1.21)
AUClast/Dose	6.48±0.33 1)	6.41±0.33 1)	0.0627	1.06
(μg.h/L/mg)			(-0.0141-0.1395)	(0.99-1.15

1) Mean ± SD of log-transformed values

2) Ratios of geometric means, glimepiride1 mg dosing group/2 mg dosing group

 

Glimepiride pharmacokinetics (Tmax and AUC) after meal was similar between a sustained-release formulation of Amaryl-M SR 2/500 mg and an immediate-release formulation of single Amaryl-M 2/500 mg or B.I.D. Amaryl-M 1/250 mg. Meanwhile, metformin tmax was delayed in sustained-release formulation compared to immediate-release formulation, but its elimination half-life was not prolonged. The extent of metformin exposure after meal was lower in sustained-release formulation than in immediate-release formulation and its B.I.D. treatment in divided doses by 14% and 23% on average respectively. This effect on exposure is not considered clinically significant as there was no significant difference in safety between treatment groups.

 

An open label, 3-period, 3-treatment, 3-way crossover study was conducted in 12 healthy Korean male subjects to evaluate the pharmacokinetic and safety profiles of Amaryl-M and Amaryl-M SR tablets. Subjects were randomized to one of 3 treatment arms (Group A, B or C). Subjects in group A received a single Amaryl-M SR 2/500 mg after breakfast. Group B received a single Amaryl-M 2/500 mg after breakfast. Group C received Amaryl-M 1/250 mg after breakfast and 12 hours later after dinner. There was a 7-day washout period between each treatment period.

 

Special populations

Glimepiride:

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.

 

Metformin:

Renal impairment:

The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to metformin in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations (see section 4.2).

 

Pediatric population

Glimepiride:

A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of glimepiride in 30 pediatric 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.

 

 

Metformin:

Single dose study: After single doses of metformin hydrochloride 500 mg pediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.

 

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in pediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycemic control, this is of limited clinical relevance

 

 

 

Glimepiride

1)      Studies in rats at doses of up to 5,000 ppm in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose related and is thought to be the result of chronic pancreatic stimulation. The No Observable Effect Level (NOEL) for adenoma formation in mice in this study was 320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area .

2)      Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies .

3)      There was no effect of glimepiride on male mouse fertility in animals exposed up to 2,500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

 

Metformin

1)      Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately three times the maximum recommended human daily dose on a body surface area basis. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day .

2)      No evidence of a mutagenic potential of metformin was found in the Ames test (S.typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberration test (human lymphocytes), or in vivo micro nuclei formation test (mouse bone marrow).

 

3)      Fertility of male or female rats was unaffected by metformin administration at doses as high as 600 mg/kg/day, or approximately two times the maximum recommended human daily dose on a body surface area basis

 

Tablet core

Lactose Monohydrate,

Sodium Starch Glycollate,

Povidone K-30,

Microcrystalline Cellulose (avicel pH 1 02),

Crospovidone,

Magnesium Stearate and

Purified Water

 

Film-Coating

Hypromellose (HPMC 2910, 6 cps),

Polyethylene Glycol MW 6000,

Titanium Dioxide (E171),

Camauba Wax and

Purified Water

Not applicable

24 months.

Do not store above 30°C.

 

Each unit carton of Amaryl M 2/500mg Film-Coated Tablets contains 30 tablets individually sealed in 3 blister strips.

 

Type of Packaging Specimen:

Primary:

Transparent thermoformed PVC/PVDC reel and hard tempered aluminium foil lid. Secondary:

Printed end opening unit carton with reverse tuck flaps and locking slits along with multi folded package insert

 

Line Applied Information:

The batch number, manufacturing date and expiry date will be imprinted on the blister strip and unit carton.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment