INSUPRID

 

TRADE NAME

Insuprid

 

INTERNATIONAL NON-PATENTED NAME

Glimepiride

 

CHEMICAL NAME

1-[[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]phenyl]sulfonyl]-3-trans-(4-methylcyclohexyl)urea.

 

PHARMACEUTICAL FORM

Tablets.

Description:

Insuprid 1 mg

Light yellow round, biconvex tablets, plain on both sides.

 

Insuprid 2 mg

Light yellow round, flat tablets with bevelled edges, plain on both sides.

 

Insuprid 3 mg

Light yellow round, biconvex tablets, plain on both sides.

 

Insuprid 4 mg

Light yellow round, flat tablets with bevelled edges, with a breakline on one side and plain on the other side.

 

COMPOSITION

Insuprid 1 mg

1 tablet contains:

Active substance: glimepiride 1 mg.

Excipients: lactose monohydrate, maize starch, iron oxide yellow, povidone К30, microcrystalline cellulose, magnesium stearate.

 

Insuprid 2 mg

1 tablet contains:

Active substance: glimepiride 2 mg.

Excipients: lactose monohydrate, maize starch, iron oxide yellow, povidone К30, microcrystalline cellulose, magnesium stearate.

 

Insuprid 3 mg

1 tablet contains:

Active substance: glimepiride 3 mg.

Excipients: lactose monohydrate, maize starch, iron oxide yellow, povidone К30, microcrystalline cellulose, magnesium stearate.

 

Insuprid 4 mg

1 tablet contains:

Active substance: glimepiride 4 mg.

Excipients: lactose monohydrate, maize starch, iron oxide yellow, povidone К30, microcrystalline cellulose, magnesium stearate.

 

АТС CODE А10ВВ12   

 

PHARMACOTHERAPEUTIC GROUP

Oral hypoglycemic agents, except insulin: sulphonylurea derivatives.

 

PHARMACOLOGIC PROPERTIES

PHARMACODYNAMICS

Insuprid is oral hypoglycemic agent, a derivative of third-generation sulphonylurea.

Glimepiride, the active substance of Insuprid, reduces blood glucose concentration, mainly through stimulation of insulin secretion from pancreatic β-cells. Its effect is primarily connected with the improvement of the pancreatic β-cells ability to respond to the physiological glucose stimulation. Compared to glibenclamide, glimepiride in low doses causes the release of fewer amounts of insulin when achieves approximately the same reduction of blood glucose concentration. This fact proves that glimepiride has extrapancreatic hypoglycemic effects (increased tissue sensitivity to insulin and insulin-mimetic effect).

Insulin secretion. Like all other sulphonylurea derivatives, glimepiride regulates insulin secretion through interaction with ATP-sensitive potassium channels on β-cell membranes. Unlike other sulphonylurea derivatives, glimepiride selectively binds to a 65 kDa protein located in membranes of pancreatic β-cells. This interaction of glimepiride with its binding protein determines the probability of ATP-sensitive potassium channels being open or closed.

Glimepiride closes the potassium channels. This causes depolarization of β-cells and results in the opening of voltage-sensitive calcium channels and calcium entry into cells. As a result, increased intracellular calcium concentration activates the secretion of insulin by exocytosis.

Glimepiride much faster and therefore more frequently binds to and releases from its binding protein than glibenclamide. This property of high exchange rate of glimepiride with its binding proteins is supposed to specify its pronounced effect of β-cell sensitization to glucose and their   protection from desensitization and early exhaustion.

The effect of increased tissue sensitivity to insulin. Glimepiride increases the effects of insulin to absorb glucose with peripheral tissues.

Insulin-mimetic effect. Glimepiride has effects similar to those of insulin to absorb glucose with peripheral tissues and release glucose from the liver.

The absorption of glucose with peripheral tissues is carried out by its transport into muscle cells and adipocytes. Glimepiride directly increases the amount of glucose-transporting molecules in plasma membranes of muscle cells and adipcytes. The increased influx of glucose into cells leads to an activation of glycosyl-phosphatidyl-inositolspecific phospholipase C. This results in a reduction in intracellular calcium levels causing a reduction in protein kinase A activity, which in its turn results in stimulation of glucose metabolism. Glimepiride inhibits hepatic glucose output by increasing the fructose-2-6-biphosphate concentration, which inhibits gluconeogenesis.

The effect on platelet aggregation and formation of atherosclerosis plaques. Glimepiride inhibits platelet aggregation in vitro and in vivo. This effect is probably the result of a selective inhibition of cyclooxygenase, which is responsible for the production of thromboxane A, an endogenous platelet aggregating factor.

Antiatherogenic action. Glimepiride contributes to lipid content normalization, reduces the blood level of malonic aldehyde, which leads to a significant reduction in lipid peroxidation.

Decrease in the severity of oxidative stress that is always present in patients with diabetes mellitus type 2. Glimepiride increases the level of endogenous α- tocopherol, the activity of catalase, glutathione peroxidase and superoxide dismutase.

Cardiovascular effects. Sulphonylurea derivatives have also effect on the cardiovascular system through ATP-sensitive potassium channel. As compared to traditional derivatives of sulphonylurea, glimepiride exerts a significantly less effect on the cardiovascular system. It decreases platelet aggregation and leads to a significant decrease in the formation of atherosclerotic plaques.

In healthy persons, the minimum effective dose of glimepiride is 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to physical exercise (reduction of insulin secretion) is preserved during glimepiride administration.

There is no significant difference in effect regardless of whether the medicinal product was given 30 minutes or immediately before a meal. In diabetic patients, adequate metabolic control over 24 hours can be achieved with a single daily dose. Moreover, in a clinical study, an adequate metabolic control was also achieved in 12 of 16 patients with renal insufficiency (creatinine clearance of 4 to 79 mL/min).

Combination therapy with metformin. A combination glimepiride therapy with metformin can be initiated in patients not adequately controlled with the maximum dosage of glimepiride. Two studies of combination therapy have proved the improvement in metabolic control as compared to that in the treatment with each of these drugs taken separately.

Combination therapy with insulin. In patients not adequately controlled with the maximum dosage glimepiride, concomitant insulin therapy can be initiated. Based on the results from two studies of this combination, the same improvement in metabolic control is achieved as with administration of insulin alone. However, a lower dose of insulin is required in combination therapy.

pharmacokinetics

When comparing data obtained with administration of single and multiple doses of glimepiride, there were no significant differences in pharmacokinetic parameters, and their variability among different patients was very low. No significant accumulation of the drug is observed.

Absorption

Its bioavailability after oral administration is complete. Food intake has no relevant influence on absorption, except for insignificant decrease in absorption rate. Peak serum concentration is reached approximately 2.5 hours after administration of multiple doses of glimepiride in a daily dose of 4 mg and makes 309 ng/mL; there is a linear relationship between dose and peak concentration, as well as between dose and AUC (area under “concentration – time” curve).

Distribution

Glimepiride has a very low volume of distribution (approximately 8.8 L), which approximately equals to that of albumin, it shows high plasma protein binding (more than 99%) and a low clearance rate (approximately 48 mL/min).

In animal studies, glimepiride was secreted in milk. It crosses the placental barrier. It poorly penetrates the blood-brain barrier.

Biotransformation and elimination

The elimination half-life, which is of relevance for the serum drug concentrations during multiple administration, is 5 to 8 hours. After high doses, a slightly longer half-life was noted.

After a single oral dose of glimepiride, 58% is recovered in urine and 35% in faeces. No unchanged substance was detected in urine. Two inactive metabolites resulting from hepatic metabolism are detected in urine and faeces, one of them is a hydroxyl derivative and the other is a carboxy derivative. After oral administration of glimepiride, the terminal half-life of these metabolites is 3 to 6 hours and 5 to 6 hours, respectively.

Pharmakokinetics in special populations

Pharmacokinetic parameters were similar in males and females, as well as in different age groups.

In patients with renal disorders (with low creatinine clearance), there is a tendency for an increase in glimepiride clearance and a decrease in its average serum concentrations, which is most probably specified by more rapid elimination due to lower protein binding. Thus, there is no additional risk of glimepiride accumulation in this category of patients.

 

 

therapeutic indicationS

- diabetes mellitus type 2 (in monotherapy or in combination with metformin or with insulin) in case of impossibility to adequately control only by diet, physical exercise or body weight reduction.

 

POSOLOGY AND ADMINISTRATION

Insuprid oral tablets.

Tablets should be swallowed whole, without chewing, washing down with sufficient amount of water (about 1/2 glass of water).

The dosage of glimepiride is determined by the results of blood and urinary glucose concentrations. The drug should be administered in minimum dose sufficient to achieve the necessary metabolic control.

The drug should be administered in minimum dose sufficient to achieve the necessary metabolic control. In addition, regular monitoring of glycosylated haemoglobin level is recommended.

Violation of the drug administration, e.g. if a dose is skipped, this should not be corrected by increasing the next dose.

The physician should instruct the patient in advance of actions to be taken when the drug is misused (in particular when the successive dose is missed or a meal is skipped), or in situations where there is no possibility to take the drug.

The starting dose of Insuprid is 1 mg once a day. If necessary, the daily dose can be gradually increased (with intervals of 1 to 2 weeks) under regular control of blood glucose level and as follows: 1 mg-2 mg-3 mg-4 mg-6 mg (-8 mg) per day.

In patients with well-controlled diabetes type 2, the usual daily dose is 1 to 4 mg. Only some patients benefit from the daily dose of 6 mg.

Timing and distribution of doses are to be decided by the physician taking into consideration the patient’s lifestyle (mealtime, amount of physical exercise). The daily dose should be taken in a single administration, generally, shortly before a substantial breakfast or - if the daily dose is not taken – shortly before the first main meal. It is very important not to skip meals after tablets have been taken.

As an improvement in metabolic control is associated with an increase in sensitivity to insulin, glimepiride requirements may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Insuprid therapy must be considered.

Treatment with glimepiride is normally a long-term therapy.

Changeover from other oral hypoglycemic agent to Insuprid

A changeover of the patient from other oral hypoglycemic agents to Insuprid is possible. Consideration must be given to the potency and duration of the previous hypoglycemic drug. In some cases, especially in administration of drugs with a long half-life (e.g., chlorpropamide), it may be necessary to interrupt the treatment to avoid additive effects that increase the risk of hypoglycaemia.

In case of changeover from other antidiabetic agents to Insuprid, the recommended starting dose of glimepiride is 1 mg (even in cases when the patient is being switched over for Insuprid from the maximum dose of other oral hypoglycemic agent). Any increase in dosage should be performed stepwise based on the response to glimepiride, as indicated above.

Changeover from insulin to Insuprid

In exceptional cases, a changeover from insulin to Insuprid may be indicated. The changeover should be undertaken under close medical supervision.

Administration in renal or hepatic impairment

There are limited data on the drug administration in patients with severe renal or hepatic impairment. In this case, a changeover to insulin is recommended.

 

 

 

CONTRAINDICATIONS

- hypersensitivity to glimepiride or any other ingredient of the drug, to other sulphonylureas or to sulfanilamide agents;

- diabetes mellitus type 1 (insulin-dependent);

- diabetic ketoacidosis, diabetic precoma and coma;

- severe hepatic and renal function disorders;

- pregnancy and lactation;

- children (no clinical experience).

 

SIDE EFFECTS

Blood and lymphatic system disorders: rare - thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia, which are in general reversible upon discontinuation of the drug.

Immune system disorders: very rare - leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into life-threatening conditions accompanied by fall in blood pressure dyspnoea, and sometimes shock.

Metabolism disorders: rare - hypoglycaemia.

These reactions mainly occur immediately after the drug administration, may be sever and are not always easy to correct. The occurrence of such reactions depends, as with other hypoglycaemic therapies, on individual factors such as dietary habits and dosage.

Eye disorders: unknown frequency - transient visual disturbances 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.

Allergic reactions: may occur in the form of itching, urticaria and photosensitivity.

Other: very rare – decreased blood sodium concentration, abnormal liver function (e.g., cholestasis or jaundice), hepatitis and hepatic failure.

 

SPECIAL INDICATIONS

When meals are taken at irregular hours or skipped altogether, treatment with glimepiride may lead to hypoglycaemia. Possible symptoms of hypoglycaemia include: headache, ravenous hunger, nausea, vomiting, fatigue, sleepiness, disordered sleep, anxiety, aggressiveness, impaired concentration, disorder of attention and reaction, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, confusion and loss of consciousness including coma, shallow respiration, and bradycardia. In addition, as a result of adrenergic counter-regulation the following symptoms may be present: cold and clammy sweat, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.

Severe or long-lasting hypoglycaemia that can only be temporarily controlled by usual amounts of sugar, requires immediate medical treatment or even hospitalization.

Treatment with glimepiride requires regular monitoring of glucose levels in blood and urine. Moreover, determination of the proportion of glycosylated haemoglobin is recommended. Regular hepatic and hematological monitoring (especially leucocytes and platelets) are also required during the treatment with glimepiride.

In stress situations (e.g. after accidents, acute operations, infections with fever, etc.) a temporary switch to insulin may be indicated.

Treatment with sulphonylurea agents can lead to hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Since glibenclamide belongs to the class of sulphonylurea derivatives, caution should be exercised in patients with glucose-6-phosphate dehydrogenase deficiency. Moreover, non-sulphonylurea alternatives should be considered.

Insuprid contains lactose monohydrate, therefore, patients with hereditary lactose intolerance, lactase deficiency or glucose-lactose malabsorption should not take this drug.

INFLUENCE ON ABILITY TO DRIVE AND OPERATE MECHANISMS

No studies on the effects on the ability to drive and operate mechanisms have been performed. The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycemia development.

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving.

 

ADMINISTRATION DURING PREGNANCY AND LACTATION

Insuprid is contraindicated in pregnancy. In case of planned pregnancy or if pregnancy occurs the patient should change over to insulin therapy.

Glimepiride is found to be excreted in milk. During lactation, woman must change over to insulin or stop breastfeeding.

 

PEDIATRIC USE

There are no data available on the use of glimepiride in children under 8 years of age. The available data on efficacy and safety are insufficient to administer glimepiride in children aged 8 to 17 years, therefore such use is not recommended.

 

interaction WITH OTHER DRUGS

Combination therapy with metformin

In patients with not adequately controlled diabetes mellitus with the maximum daily dose of glimepiride or metformin, concomitant therapy can be initiated. The previous treatment either with glimepiride, or metformin should be continued in the same doses, and additional administration of metformin or glimepiride is to be started with a low dose that 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.

Combination therapy with insulin

In patients with not adequately controlled diabetes mellitus with the maximum daily dose of glimepiride, concomitant insulin therapy can be initiated. In this case, the current dose of glimepiride remains unchanged. Insulin treatment is started at low doses that are subsequently increased stepwise under control of blood glucose concentration. The combination therapy should be carried out under close medical supervision. While maintaining long-term glycemic control this combination therapy can reduce insulin requirements by approximately 40%.

Glimepiride is metabolized by cytochrome Р4502С9, which should be taken into account in concomitant administration with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole).

Results from an in vivo interaction study reported in literature show that glimepiride AUC is increased approximately 2-fold by fluconazole, one of the most potent CY32C9 inhibitors.

Potentiation of hypoglycemic effect and, thus, possible development of hypoglycaemia may occur in concomitant administration of glimepiride with angiotensin converting enzyme (ACE) inhibitors, allopurinol, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclo-, tro- and isophosphamides, fenfluramine, fenyramidol, fibrates, fluoxetine, sympatholytics (guanethidine), monoaminooxidase (MAO) inhibitors, miconazole, fluconazole, pentoxifylline (high dose parenteral), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolones, salicylates and aminosalicylic acid, some long-acting sulfanilamide, tetracyclines, tritoqualine.

Weakening of hypoglycemic effect and, thus, raised blood glucose levels may occur in concomitant administration of glimepiride with acetazolamide, barbiturates, glucocorticoids, diazoxide, saluretics, thiazide diuretics, epinephrine and other sympathicomimetics, glucagon, laxatives (long term use), nicotinic acid (high dosages) and nicotinic acid derivatives, oestrogens and progestogens, phenothiazines, chlorpromazine, phenytoin, rifampicin, thyroid hormones, lithium salts.

Н₂-receptor blockers, clonidine and reserpine can both potentiate and weaken the hypoglycemic effect of glimepirideа.

Glimepiride may either potentiate or weaken the effects of coumarin derivatives.

Either single or chronic alcohol intake may potentiate or weaken the hypoglycemic action of glimepiride.

 

OVERDOSE

Overdose with sulphonylurea derivatives, including Insuprid, may lead to hypoglycaemia. Symptoms of moderate hypoglycaemia, without loss of consciousness or other neurological disorders, can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar lump, sugar sweetened fruit juice or tea). In some cases, gastric lavage and administration of charcoal may be required to prevent the drug absorption. Unless the physician decides that the patient is out of danger, the patient must be under close medical supervision.

Significant overdose and severe reactions with such manifestations as loss of consciousness or severe neurological disorders are medical emergencies and require immediate treatment and hospitalization. Intravenous injection of concentrated 50% glucose solution is required in case of loss of consciousness. Then it is necessary to continue injection of 10% glucose solution to reach glucose level of above 100 mg/dL. The blood glucose concentration in such patients should be continuously monitored for 24-48 hours as repeated hypoglycemia is possible.

 

PACKAGING

10 tablets are in a blister.

3 blisters are in a carton box with an insert leaflet.

 

storage conditions

Store at temperature not exceeding 25ºС.

Keep out of reach of children!

 

SHELF LIFE

3 years from the date of manufacture.

Do not use after the expiry date.

 

SALES TERMS

Sold under prescription.

MANUFACTURER

The holder of trade mark and Marketing Authorization is

“INSUPHAR LABORATORIES LIMITED”, GREAT BRITAIN.

Manufactured by

“LABORATOIRE BAILLY-CREAT”, Chemin de Nuisement Z.I. des 150 Аrpents, 28500 Vernouillet, France under licence by “MEDREICH”, Great Britain.