Composition: each tablet contains glimepiride 1mg- 2mg- 4mg.

Pharmacological properties:

AMARAX (glimepiride) is an oral blood-glucose-lowering drug of the sulfonylurea class. The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin.

Pharmacokinetics:                                                                    

After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%, Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). When 14C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces.

Indications:

AMARAX is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications:

AMARAX is contraindicated in patients with:

1.Known hypersensitivity to the drug.

2.Diabetic ketoacidosis, with or without coma.

3. Sulphonylureas should be avoided where possible in severe hepatic impairment and in acute porphyria
4. they shouldn’t be used during pregnancy and while breast-feeding .

Warnings and precautions:

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.

Persons allergic to other sulfonamide derivatives may develop an allergic reaction to glimepiride as well.

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of AMARAX. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to add insulin in combination with AMARAX or even use insulin monotherapy.

The effectiveness of any oral hypoglycemic drug, including AMARAX, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, Should secondary failure occur with AMARAX or metformin monotherapy, combined therapy with AMARAX and metformin or AMARAX and insulin may result in a response.

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Since AMARAX belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycemic control.

Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite adequate attempts at dieting. Metformin is considered the drug of choice in obese patient . Caution is needed in the elderly and in those with mild to moderate hepatic impairment because of hazard of hypoglycaemia .

Use in pregnancy:

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, AMARAX (glimepiride) should not be used during pregnancy. Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities.

Nursing mothers:

Because the potential for hypoglycemia in nursing infants may exist AMARAX should be discontinued in nursing mothers.

Pediatrics:

Data are insufficient to recommend pediatric use of AMARAX.

Drug interactions:

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs, clarithromycin, disopyramide, fluoxetine,cimetidine , testosterone , and quinolones and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When these drugs are administered to a patient receiving AMARAX, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving AMARAX, the patient should be observed closely for loss of glycemic control.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, progestogens , phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving AMARAX, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving AMARAX, the patient should be observed closely for hypoglycemia.

Coadministration of aspirin (1 g tid) and AMARAX led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean Cmax had a decrease of 4%.

Concomitant administration of propranolol (40 mg tid) and AMARAX significantly increased Cmax, AUC, and T½ of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/f by 18%.

There is a potential interaction of glimepiride with inhibitors (e.g. fluconazole) and inducers (e.g. rifampicin) of cytochrome P450 2C9..

Plasma concentration of sulphonylureas increased by fluconazole, miconazole and voriconazole.

Requirements for sulphonylureas possibly reduced by lanreotide and octreotide .

Adverse reactions:

The administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.

The incidence of  hypoglycemia with amarax (blood glucose values <60mg/dl ) ranged from 0.9-1.7% .dizziness, asthenia ,headache , nausia and vomiting, gastrointestinal pain, and diarrhea. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure  , Allergic skin reactions, e.g., pruritus, erythema, urticaria, Porphyria, photosensitivity reactions, and allergic vasculitis, Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, , Hepatic porphyria reactions and disulfiram-like reactions, hyponatremia, (SIADH)The syndrome of inappropriate antidiuretic hormone , Changes in accommodation and/or blurred vision.

Severe allergic reactions (difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain or irregular heartbeat; dark urine; fainting; fever, chills, or persistent sore throat.

Overdosage:

Overdosage of sulfonylureas, including AMARAX, can produce hypoglycemia. Mild hypoglycemic symptoms 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. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.

Dosage:

Usual Starting Dose: The usual starting dose of AMARAX as initial therapy is 1-2 mg once daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1 mg once daily, and should be titrated carefully. The maximum starting dose of AMARAX should be no more than 2 mg.

Usual Maintenance Dose :The usual maintenance dose is 1 to 4 mg once daily. The maximum recommended dose is 8 mg  once daily. After reaching a dose of 2 mg, dosage increases should be made in increments of no more than 2 mg at 1-2 week intervals based upon the patient’sblood glucose response  long term efficacy should be monitored by measurement of HbA1c levels, for example, every 3 to 6 months.

AMARAX-Metformin Combination Therapy: If patients do not respond adequately to the maximal dose of AMARAX monotherapy, addition of metformin may be considered. With concomitant AMARAX and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.

AMARAX-Insulin Combination Therapy:

Combination therapy with AMARAX and insulin may also be used in secondary failure patients. The fasting glucose level for instituting combination therapy is in the range of > 150 mg/dL in plasma or serum depending on the patient. The recommended AMARAX dose is 8 mg once daily administered with the first main meal. After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily. Periodic adjustments of insulin may also be necessary during maintenance as guided by glucose and HbA1c levels.

packing:

• AMARAX 1 contains glimepiride 1 mg.: pack of 20-30 tablets.
• AMARAX 1 contains glimepiride 2 mg.: pack of 20-30 tablets.
• AMARAX 1 contains glimepiride 4 mg.: pack of 20-30 tablets.

Storage: Store between  (15 and 30 ° C).