Amaryl^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis Deutschland, GmbH (Germany)

Manufactured By

Sanofi, S.p.A. (Italy)

Contact Information

SANOFI

ATC Code

A10BB12 (Glimepiride)

Active Substance

Glimepiride (Rec.INN registered by WHO)

Dosage Forms

	Amaryl®	Tablets 1 mg: 30, 60, 90 or 120 pcs.
		Tablets 2 mg: 30, 60, 90 or 120 pcs.
		Tablets 3 mg: 30, 60, 90 or 120 pcs.
		Tablets 4 mg: 30, 60, 90 or 120 pcs.

Dosage Form, Packaging, and Composition

Tablets are pink, oblong, flat, with a score line on both sides, engraved with “NMK” and a stylized “h” on two sides.

Excipients: lactose monohydrate, sodium carboxymethyl starch (type A), povidone 25,000, microcrystalline cellulose, magnesium stearate, iron oxide red dye (E172).

15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.
15 pcs. – blisters (6) – cardboard packs.
15 pcs. – blisters (8) – cardboard packs.

Tablets are green, oblong, flat, with a score line on both sides, engraved with “NMM” and a stylized “h” on two sides.

Excipients: lactose monohydrate, sodium carboxymethyl starch (type A), povidone 25,000, microcrystalline cellulose, magnesium stearate, iron oxide yellow dye (E172), indigo carmine (E132).

15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.
15 pcs. – blisters (6) – cardboard packs.
15 pcs. – blisters (8) – cardboard packs.

Tablets are pale yellow, oblong, flat, with a score line on both sides, engraved with “NMN” and a stylized “h” on two sides.

Excipients: lactose monohydrate, sodium carboxymethyl starch (type A), povidone 25,000, microcrystalline cellulose, magnesium stearate, iron oxide yellow dye (E172).

15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.
15 pcs. – blisters (6) – cardboard packs.
15 pcs. – blisters (8) – cardboard packs.

Tablets are blue, oblong, flat, with a score line on both sides, engraved with “NMO” and a stylized “h” on two sides.

Excipients: lactose monohydrate, sodium carboxymethyl starch (type A), povidone 25,000, microcrystalline cellulose, magnesium stearate, indigo carmine (E132).

15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.
15 pcs. – blisters (6) – cardboard packs.
15 pcs. – blisters (8) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent for oral administration of the third-generation sulfonylurea group

Pharmacological Action

An oral hypoglycemic drug – a sulfonylurea derivative of the third generation.

Glimepiride reduces blood glucose concentration, mainly by stimulating the release of insulin from pancreatic beta cells. Its effect is primarily associated with improving the ability of pancreatic beta cells to respond to physiological glucose stimulation. Compared to glibenclamide, Glimepiride in low doses causes the release of less insulin while achieving approximately the same reduction in blood glucose concentration. This fact indicates the presence of extrapancreatic hypoglycemic effects in glimepiride (increased tissue sensitivity to insulin and an insulinomimetic effect).

Insulin secretion. Like all other sulfonylurea derivatives, Glimepiride regulates insulin secretion by interacting with ATP-sensitive potassium channels on beta cell membranes. Unlike other sulfonylurea derivatives, Glimepiride selectively binds to a protein with a molecular weight of 65 kilodaltons located in the membranes of pancreatic beta cells. This interaction of glimepiride with its binding protein regulates the opening or closing of ATP-sensitive potassium channels.

Glimepiride closes potassium channels. This causes depolarization of beta cells and leads to the opening of voltage-sensitive calcium channels and the influx of calcium into the cell. As a result, the increase in intracellular calcium concentration activates insulin secretion through exocytosis.

Glimepiride binds and is released from its binding protein much faster and more frequently than glibenclamide. It is assumed that this property of high exchange rate of glimepiride with its binding protein determines its pronounced effect of sensitizing beta cells to glucose and protecting them from desensitization and premature exhaustion.

Effect of increasing tissue sensitivity to insulin. Glimepiride enhances the effects of insulin on glucose uptake by peripheral tissues.

Insulinomimetic effect. Glimepiride has effects similar to those of insulin on glucose uptake by peripheral tissues and glucose output from the liver.

Glucose uptake by peripheral tissues is carried out by its transport into muscle cells and adipocytes. Glimepiride directly increases the number of glucose-transporting molecules in the plasma membranes of muscle cells and adipocytes. The increased intracellular glucose influx leads to the activation of glycosylphosphatidylinositol-specific phospholipase C. As a result, the intracellular calcium concentration decreases, causing a reduction in protein kinase A activity, which in turn stimulates glucose metabolism.

Glimepiride inhibits glucose output from the liver by increasing the concentration of fructose-2,6-bisphosphate, which inhibits gluconeogenesis.

Effect on platelet aggregation. Glimepiride reduces platelet aggregation in vitro and in vivo. This effect appears to be associated with selective inhibition of COX, which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor.

Antiatherogenic action. Glimepiride promotes the normalization of lipid content, reduces the level of malondialdehyde in the blood, leading to a significant decrease in lipid peroxidation. In animals, Glimepiride leads to a significant reduction in the formation of atherosclerotic plaques.

Reduction of oxidative stress, which is constantly present in patients with type 2 diabetes mellitus. Glimepiride increases the level of endogenous alpha-tocopherol, activity of catalase, glutathione peroxidase, and superoxide dismutase.

Cardiovascular effects. Through ATP-sensitive potassium channels, sulfonylurea derivatives also affect the cardiovascular system. Compared to traditional sulfonylurea derivatives, Glimepiride has a significantly lesser effect on the cardiovascular system, which may be explained by the specific nature of its interaction with the binding protein of ATP-sensitive potassium channels.

In healthy volunteers, the minimum effective dose of glimepiride is 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to physical exertion (decreased insulin secretion) is preserved when taking glimepiride.

There are no significant differences in the effect depending on whether the drug was taken 30 minutes before a meal or immediately before a meal. In patients with diabetes mellitus, adequate metabolic control can be achieved within 24 hours with a single dose of the drug. Moreover, in a clinical study, 12 out of 16 patients with renal failure (creatinine clearance 4-79 ml/min) also achieved adequate metabolic control.

Combination therapy with metformin. In patients with inadequate metabolic control when using the maximum dose of glimepiride, combination therapy with glimepiride and metformin may be initiated. In two studies, combination therapy demonstrated improved metabolic control compared to treatment with each of these drugs separately.

Combination therapy with insulin. In patients with inadequate metabolic control when taking glimepiride in maximum doses, simultaneous therapy with insulin may be initiated. According to the results of two studies, this combination achieves the same improvement in metabolic control as with insulin alone. However, combination therapy requires a lower dose of insulin.

Pharmacokinetics

When comparing data obtained from single and multiple (once daily) administration of glimepiride, no significant differences in pharmacokinetic parameters were revealed, and their variability between different patients was very low. There is no significant accumulation of the drug.

Absorption

With multiple oral administration of the drug at a daily dose of 4 mg, C_max in blood serum is reached in approximately 2.5 hours and is 309 ng/ml. There is a linear relationship between the dose and C_max of glimepiride in plasma, as well as between the dose and AUC. When taken orally, the bioavailability of glimepiride is 100%. Food intake does not have a significant effect on absorption, except for a slight delay in its rate.

Distribution

Glimepiride is characterized by a very low V_d (about 8.8 L), approximately equal to the V_d of albumin, a high degree of binding to plasma proteins (more than 99%), and a low clearance (about 48 ml/min).

Glimepiride is excreted in breast milk and crosses the placental barrier.

Metabolism

Glimepiride is metabolized in the liver (mainly by the CYP2C9 isoenzyme) to form 2 metabolites – hydroxylated and carboxylated derivatives, which are found in urine and feces.

Excretion

T_1/2 at plasma drug concentrations in serum corresponding to the multiple dosing regimen is approximately 5-8 hours. After taking high doses of glimepiride, T_1/2 increases somewhat.

After a single oral dose, 58% of glimepiride is excreted by the kidneys and 35% through the intestines. The unchanged active substance is not detected in the urine.

The T_1/2 of the hydroxylated and carboxylated metabolites of glimepiride were about 3-5 hours and 5-6 hours, respectively.

Pharmacokinetics in special clinical situations

Pharmacokinetic parameters are similar in patients of different sexes and different age groups.

In patients with impaired renal function (with low creatinine clearance), there is a tendency for an increase in the clearance of glimepiride and a decrease in its mean serum concentrations, which is most likely due to faster elimination of the drug due to its lower protein binding. Thus, there is no additional risk of glimepiride accumulation in this category of patients.

Indications

• Type 2 diabetes mellitus (as monotherapy or as part of combination therapy with metformin or insulin).

ICD codes

Dosage Regimen

As a rule, the dose of Amaryl^® is determined by the target blood glucose concentration. The drug should be used at the minimum dose sufficient to achieve the necessary metabolic control.

During treatment with Amaryl^®, blood glucose levels must be regularly determined. In addition, regular monitoring of glycated hemoglobin levels is recommended.

A violation of drug intake, for example, missing a dose, should not be compensated for by a subsequent higher dose of the drug.

The physician should instruct the patient in advance about the actions to be taken in case of errors in taking Amaryl^® (in particular, missing a dose or a meal), or in situations where it is not possible to take the drug.

Amaryl^® tablets should be taken whole, without chewing, with a sufficient amount of liquid (about 1/2 glass). If necessary, Amaryl^® tablets can be divided along the score line into two equal parts.

The initial dose of Amaryl^® is 1 mg once daily. If necessary, the daily dose can be gradually increased (at intervals of 1-2 weeks) under regular monitoring of blood glucose levels and in the following order: 1 mg-2 mg-3 mg-4 mg-6 mg (-8 mg) per day.

In patients with well-controlled type 2 diabetes mellitus, the daily dose of the drug is usually 1-4 mg. A daily dose of more than 6 mg is more effective only in a small number of patients.

The time of taking Amaryl^® and the distribution of doses during the day is determined by the physician taking into account the patient’s lifestyle (meal times, amount of physical activity). The daily dose is prescribed in one dose, usually immediately before a full breakfast or, if the daily dose was not taken, immediately before the first main meal. It is very important not to skip a meal after taking Amaryl^® tablets.

Since improved metabolic control is associated with increased insulin sensitivity, the need for glimepiride may decrease during treatment. To avoid the development of hypoglycemia, it is necessary to reduce the dose or discontinue Amaryl^® in a timely manner.

Conditions in which dose adjustment of glimepiride may also be required

• Weight loss;
• Changes in lifestyle (changes in diet, meal times, amount of physical activity);
• The occurrence of other factors that lead to a predisposition to the development of hypoglycemia or hyperglycemia.

Treatment with glimepiride is usually long-term.

Transferring a patient from another oral hypoglycemic drug to Amaryl^®

There is no exact ratio between the doses of Amaryl^® and other oral hypoglycemic drugs. When transferring from such drugs to Amaryl^®, the recommended initial daily dose of the latter is 1 mg (even if the patient is transferred to Amaryl^® from the maximum dose of another oral hypoglycemic drug). Any dose increase should be carried out stepwise, taking into account the response to Glimepiride in accordance with the recommendations above. The intensity and duration of the effect of the previous hypoglycemic agent must be taken into account. An interruption of treatment may be required to avoid an additive effect that increases the risk of hypoglycemia.

Use in combination with metformin

In patients with inadequately controlled diabetes mellitus when taking glimepiride or metformin at maximum daily doses, treatment with a combination of these two drugs may be initiated. In this case, the previous treatment with either glimepiride or metformin is continued at the same doses, and the additional intake of metformin or glimepiride is started at a low dose, which is then titrated depending on the target level of metabolic control, up to the maximum daily dose. Combination therapy should be initiated under strict medical supervision.

Use in combination with insulin

Patients with inadequately controlled diabetes mellitus when taking glimepiride at the maximum daily dose may be simultaneously prescribed insulin. In this case, the last prescribed dose of glimepiride remains unchanged. Insulin therapy is started at low doses, which are gradually increased under the control of blood glucose concentration. Combined treatment is carried out under careful medical supervision.

Patients with impaired renal function may be more sensitive to the hypoglycemic effect of glimepiride. Data on the use of Amaryl^® in patients with renal failure are limited.

Data on the use of Amaryl^® in patients with hepatic insufficiency are limited.

Adverse Reactions

From the metabolic system, hypoglycemia is possible, which, as with the use of other sulfonylurea derivatives, can be prolonged. Symptoms of hypoglycemia – headache, feeling of hunger, nausea, vomiting, feeling of fatigue, drowsiness, sleep disturbances, anxiety, aggressiveness, impaired concentration, alertness and speed of reactions, depression, confusion, speech disorders, aphasia, visual disturbances, tremor, paresis, sensory disturbances, dizziness, loss of self-control, delirium, cerebral convulsions, drowsiness or loss of consciousness up to coma, shallow breathing, bradycardia. In addition, manifestations of adrenergic counter-regulation in response to hypoglycemia may occur, such as the appearance of cold clammy sweat, anxiety, tachycardia, arterial hypertension, angina pectoris, palpitations, and cardiac arrhythmias. The clinical picture of severe hypoglycemia may resemble a stroke. Symptoms of hypoglycemia almost always disappear after its elimination.

From the organ of vision, transient visual disturbances are possible (especially at the beginning of treatment), due to changes in blood glucose concentration. Their cause is a temporary change in the swelling of the lenses, depending on the blood glucose concentration, and thus a change in the refractive index of the lenses.

From the digestive system: rarely – nausea, vomiting, feeling of heaviness or fullness in the epigastrium, abdominal pain, diarrhea; in some cases – hepatitis, increased activity of liver enzymes and/or cholestasis and jaundice, which may progress to life-threatening liver failure, but may reverse upon discontinuation of the drug.

Hematopoietic system disorders: rarely – thrombocytopenia; in some cases – leukopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis, and pancytopenia. During post-marketing use of the drug, cases of severe thrombocytopenia with platelet count <10,000/µl and thrombocytopenic purpura have been reported (frequency unknown).

Allergic reactions rarely – allergic and pseudoallergic reactions, such as pruritus, urticaria, skin rash. Such reactions are almost always mild, however, they may progress to severe reactions with dyspnea, sharp decrease in blood pressure, which sometimes progress up to anaphylactic shock; in some cases – allergic vasculitis.

Other in some cases – hyponatremia, photosensitivity.

If symptoms of urticaria appear, you should immediately consult a doctor.

Contraindications

• Type 1 diabetes mellitus;
• Diabetic ketoacidosis, diabetic precoma and coma;
• Severe liver dysfunction (no clinical experience of use);
• Severe renal impairment, including patients on hemodialysis (no clinical experience of use);
• Pregnancy;
• Lactation (breastfeeding);
• Childhood (no clinical experience of use);
• Rare hereditary diseases such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption;
• Hypersensitivity to the drug components;
• Hypersensitivity to other sulfonylurea derivatives and sulfonamide drugs (risk of hypersensitivity reactions).

Use with caution during the first weeks of treatment (increased risk of hypoglycemia); in the presence of risk factors for hypoglycemia (dose adjustment of glimepiride or the entire therapy may be required); during intercurrent illnesses while on treatment or when the patient’s lifestyle changes (changes in diet and meal times, increase or decrease in physical activity); in glucose-6-phosphate dehydrogenase deficiency; in cases of impaired absorption of food and drugs from the gastrointestinal tract (intestinal obstruction, intestinal paresis).

Use in Pregnancy and Lactation

Amaryl^® is contraindicated for use during pregnancy. In case of planned pregnancy or if pregnancy occurs, the woman should be switched to insulin therapy.

It has been established that Glimepiride is excreted in breast milk. During lactation, the woman should be switched to insulin or breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use in Renal Impairment

Contraindicated in severe renal impairment (including patients on hemodialysis);

Pediatric Use

Contraindicated in childhood.

Special Precautions

In special clinical stress conditions, such as trauma, surgical interventions, infections accompanied by fever, metabolic control may worsen in patients with diabetes mellitus, therefore, a temporary switch to insulin therapy may be required to maintain adequate metabolic control.

During the first weeks of treatment, there may be an increased risk of hypoglycemia, which requires particularly careful monitoring of blood glucose concentration.

Factors contributing to the risk of hypoglycemia include

• Unwillingness or inability of the patient (more common in elderly patients) to cooperate with the doctor;
• Malnutrition, irregular meals or missed meals;
• Imbalance between physical activity and carbohydrate intake;
• Diet changes;
• Alcohol consumption, especially when combined with missed meals;
• Severe renal impairment;
• Severe liver dysfunction (in patients with severe liver dysfunction, switching to insulin therapy is indicated, at least until metabolic control is achieved);
• Overdose of glimepiride;
• Some decompensated endocrine disorders affecting carbohydrate metabolism or adrenergic counter-regulation in response to hypoglycemia (e.g., some thyroid and anterior pituitary disorders, adrenal insufficiency);
• Concomitant use of certain drugs;
• Use of glimepiride in the absence of indications for its use.

Treatment with sulfonylurea derivatives, which include Glimepiride, can lead to the development of hemolytic anemia, therefore, in patients with glucose-6-phosphate dehydrogenase deficiency, special caution should be exercised when prescribing glimepiride; it is preferable to use hypoglycemic agents that are not sulfonylurea derivatives.

In the presence of the above-mentioned risk factors for hypoglycemia, as well as in the event of intercurrent illnesses during treatment or changes in the patient’s lifestyle, adjustment of the glimepiride dose or the entire therapy may be required.

Symptoms of hypoglycemia resulting from the body’s adrenergic counter-regulation in response to hypoglycemia may be mild or absent in cases of gradual development of hypoglycemia, in elderly patients, in patients with autonomic nervous system disorders, or in patients receiving beta-blockers, clonidine, reserpine, guanethidine, and other sympatholytic agents.

Hypoglycemia can be quickly eliminated by immediate intake of rapidly absorbed carbohydrates (glucose or sucrose). As with the intake of other sulfonylurea derivatives, despite initial successful relief of hypoglycemia, hypoglycemia may recur. Therefore, patients should remain under constant observation. In severe hypoglycemia, immediate medical treatment and observation are additionally required, and in some cases, hospitalization of the patient.

During treatment with glimepiride, regular monitoring of liver function and peripheral blood picture (especially leukocyte and platelet counts) is required.

Such side effects as severe hypoglycemia, serious blood count changes, severe allergic reactions, liver failure can be life-threatening, therefore, in case of such reactions, the patient must immediately inform the attending physician, discontinue the drug and not resume taking it without a doctor’s recommendation.

Use in pediatrics

Data on the long-term efficacy and safety of the drug in children are not available.

Effect on ability to drive vehicles and operate machinery

At the beginning of treatment, after a change in treatment, or with irregular intake of glimepiride, decreased concentration and speed of psychomotor reactions due to hypo- or hyperglycemia may be noted. This may adversely affect the ability to drive a car or operate various machines and mechanisms.

Overdose

Symptoms in acute overdose, as well as during long-term treatment with excessively high doses of glimepiride, severe life-threatening hypoglycemia may develop.

Treatment hypoglycemia can almost always be quickly relieved by immediate intake of carbohydrates (glucose or a piece of sugar, sweet fruit juice or tea). In this regard, the patient should always carry at least 20 g of glucose (4 pieces of sugar). Sugar substitutes are not effective in treating hypoglycemia.

Until the doctor decides that the patient is out of danger, the patient requires careful medical supervision. It should be borne in mind that hypoglycemia may recur after the initial restoration of blood glucose concentration.

If a patient with diabetes mellitus is treated by different doctors (for example, during a hospital stay after an accident, illness on weekends), he must be sure to inform them about his disease and previous treatment.

Sometimes hospitalization of the patient may be required, even as a precautionary measure. Significant overdose and severe reaction with manifestations such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and hospitalization.

In case of loss of consciousness, intravenous administration of a concentrated dextrose (glucose) solution is necessary (for adults, starting with 40 ml of a 20% solution). As an alternative for adults, intravenous, subcutaneous or intramuscular administration of glucagon is possible, for example, in a dose of 0.5-1 mg.

When treating hypoglycemia due to accidental intake of Amaryl^® by infants or young children, the dose of dextrose should be carefully adjusted to avoid the possibility of dangerous hyperglycemia; dextrose administration should be carried out under constant monitoring of blood glucose concentration.

In case of Amaryl^® overdose, gastric lavage and intake of activated charcoal may be required.

After rapid restoration of blood glucose concentration, intravenous infusion of a dextrose solution in a lower concentration is mandatory to prevent recurrence of hypoglycemia. Blood glucose concentration in such patients should be constantly monitored for 24 hours. In severe cases with a prolonged course of hypoglycemia, the danger of decreased blood glucose levels may persist for several days.

As soon as an overdose is detected, it is necessary to urgently inform the doctor.

Drug Interactions

Glimepiride is metabolized with the participation of the CYP2C9 isoenzyme, which should be taken into account when using the drug concomitantly with inducers (e.g., rifampicin) or inhibitors (e.g., fluconazole) of CYP2C9.

Potentiation of the hypoglycemic effect and in some cases the associated possible development of hypoglycemia may be observed when Amaryl^® is combined with one of the following drugs: insulin, other oral hypoglycemic agents, ACE inhibitors, anabolic steroids and androgens, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, phenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, fluconazole, PAS, pentoxifylline (high parenteral doses), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, clarithromycin, sulfonamides, tetracyclines, tritoqualine, trophosphamide.

Decrease in the hypoglycemic effect and the associated increase in blood glucose concentration is possible when combined with one of the following drugs: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, sympathomimetic agents (including epinephrine), glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogens and progestogens, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones.

Histamine H₂-receptor blockers, beta-blockers, clonidine, and reserpine can either enhance or reduce the hypoglycemic effect of glimepiride.

Under the influence of sympatholytic agents, such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of adrenergic counter-regulation in response to hypoglycemia may be reduced or absent.

During glimepiride intake, the effect of coumarin derivatives may be enhanced or weakened.

Single or chronic alcohol consumption can either enhance or weaken the hypoglycemic effect of glimepiride.

Bile acid sequestrants: colesevelam binds to glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. If glimepiride is taken at least 4 hours before oral intake of colesevelam, no interaction is observed. Therefore, Glimepiride must be taken at least 4 hours before taking colesevelam.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.