Pharmacology

Pharmacodynamics

Glimepiride
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 sulphonylureas such as glimepiride.

Metformin
Metformin is an oral antihyperglyacemic drug used in the management of type 2 diabetes. It improves glucose tolerance in patients with type 2 diabetes (NIDDM), lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically related to sulphonylureas, thiazolidinediones, or µ -glucosidase inhibitors. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacokinetics

Absorption
Glimepiride
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 NIDDM have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (C max ) at 2 to 3 hours. When glimepiride was given with meals, the mean T max (time to reach C max ) was slightly increased (12%) and the mean C max and AUC (area under the curve) were slightly decreased (8% and 9%, respectively).

Metformin extended release
The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Following a single oral dose of metformin extended release; C max is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin immediate release, however, the extent of absorption (as measured by AUC) is similar to immediate release.

At steady state, the AUC and C max are less than dose proportional for extended release within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 µg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from extended release at a 2000 mg once-daily dose is similar to the same total daily dose administered as immediate release tablets 1000 mg twice daily. After repeated administration of extended release, metformin did not accumulate in plasma. Within subject variability in C max and AUC of metformin from extended release is comparable to that with immediate release.

Although the extent of metformin absorption (as measured by AUC) from the extended release tablet increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of extended release.

Distribution

Glimepiride
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%.

Metformin extended release
Distribution studies with metformin extended release have not been conducted. However, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulphonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 µg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Metabolism
Glimepiride
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). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.

Metformin extended release
Metabolism studies with metformin extended release have not been conducted.

Excretion
Glimepiride
When 14 C-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 faeces and M1 and M2 (predominant) accounted for about 70% of that recovered in faeces. No parent drug was recovered from urine or faeces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

Metformin
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Indications

Exermet GM is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes who are already treated with a combination of glimepiride and metformin or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to glimepiride alone and require additional glycaemic control.

Dosage And Administration

General
Dosage should be individualized on the basis of both effectiveness and tolerance. The combination should be given once daily with meals and should be started at a low dose. The initial recommended dose is one tablet once daily with breakfast or first main meal of the day.

Starting dose for patients inadequately controlled on metformin monotherapy

Based on the usual starting dose of glimepiride (1-2 mg daily), Exermet GM 501 or Exermet GM 502 may be initiated once daily, and gradually titrated after assessing adequacy of therapeutic response.

Starting dose for patients who initially responded to glimepiride monotherapy and require additional glycaemic control

Based on the usual starting doses of metformin extended release (500 mg once daily), Exermet GM 501 or Exermet GM 502 may be initiated once daily, and gradually titrated after assessing adequacy of therapeutic response .

Starting dose for patients switching from combination therapy of glimepiride plus metformin as separate tablets

Exermet GM 501 or Exermet GM 502 may be initiated based on the dose of glimepirde and metformin already being taken.

Maximum Recommended Dose
The maximum recommended dose for glimiperide is 8 mg daily. The maximum recommended daily dose for metformin is 2550 mg in adults.

Contraindications

Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ³ 1.5 mg/dL [males], ³ 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.

Congestive heart failure requiring pharmacologic treatment.

Known hypersensitivity to this product or any of its components.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Warnings and Precautions

Cardiac effects

The administration of oral hypoglycemic drugs (tolbutamide) has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. In view of close similarities between the oral hypoglyacemic drugs, this warning also applies for glimepiride.

Lactic acidosis

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with glimepiride and metformin combination therapy; when it occurs, it is fatal in approximately 50% of cases. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency and congestive heart failure.

General

Hypoglycaemia
All sulphonylurea drugs are capable of producing severe hypoglycaemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycaemic episodes.

Loss of control of blood glucose
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycaemic control may occur. At such times, it may be necessary to withhold the diabetic regime and temporarily administer insulin. The oral antidiabetic therapy may be reinstituted after the acute episode is resolved.

Surgical procedures
Oral antidiabetic therapy 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.  

Alcohol intake
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin.

Drug Interactions

Cationic drugs : Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretions (e.g: amiloride, cimetidine , digoxin, morphine, procainamide, quinidine, ranitidine, or vancomycin) may decrease metformin elimination by competing for common renal tubular transport systems. Hence, careful patient monitoring and dose adjustment of metformin and/or interfering cationic drug is recommended.

Miconazole (systemic route, oromucosal gel) and Phenylbutazone (systemic route): Increases hypoglycaemic effect of glimepiride.

Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max 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 and furosemide when co-administered chronically.

Vitamin B 12 : Metformin may result in suboptimal oral vitamin B 12 absorption by competitively blocking the calcium dependent binding of the intrinsic factor vitamin B 12 complex to its receptor. The reaction very rarely results in pernicious anaemia that is reversible with discontinuation of metformin or with vitamin B 12 supplementation.

Nifedepine: Nifedepine appears to enhances the absorption of metformin, it increases plasma metformin C max and AUC by 20% and 9% respectively and increases the amount of metformin excreted in the urine. Metformin has minimal effects on nifedepine.

Danzol: If the use of this active substance cannot be avoided, warn the patients and emphasise the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of glimepiride and metformin during and after treatment with danazol.

Salicylates: If salicylates are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycaemia or loss of blood glucose control.

Thiazide: Interactions between thiazide diuretics and oral antidiabetic agents decreases insulin sensitivity thereby leading to glucose intolerance and hyperglycaemia, thus leading to a loss of diabetic control. Hence diabetic patients should be monitored closely.

Other: Concomitant administration of angiotensin enzyme inhibitors (captopril,enalapril), other antidiabetic drugs (insulin, acarbose) beta-blockers, fluconozole, histamine (H 2 ) receptor antagonist, monoamine oxidase inhibitors (MAOIs), sulphonamides and non-steroidal anti-inflamatory agents increases sensitivity to insulin and potentiation of blood glucose lowering effect and thus ,in some instances, hypoglycaemia may occur . Dosage of the oral antidiabetic agent may need to be reduced. Patients receiving estrogens or oral contraceptives, phenytoin, quinolones should be closely monitored for loss of diabetic control when therapy is instituted or discontinued.

Renal impairment

The use of glimepiride and metformin is contraindicated in patients with renal impairment.

Hepatic impairment

The use of glimepiride and metformin is contraindicated in patients with hepatic impairment.

Pregnancy

Recent information suggested that abnormal blood glucose levels during pregnancy are associated with the higher incidence of congenital abnormalities. Most experts suggest insulin be used to maintain the blood glucose levels as close to normal as possible. The use of glimepiride and metformin combination is not recommended for use in pregnancy.

Lactation

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted on nursing mothers. Glimepiride should not be used by breast-feeding mothers. Hence, the use of glimepiride and metformin combination is not recommeneded for use in lactating mothers, and if the diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Paediatric use

Safety and effectiveness of glimepiride and metformin combination in paediatric patients have not been established.

Geriatric use

Metformin is know to be excreted by the kidneys, and because risk of serious adverse reactions to the drug is greater in patients with impaired renal function, hence glimepiride and metformin should be used only in patients with normal renal function. Because aging is associated with reduced renal function the use of glimepiride and metformin combination should be with caution as age increases. Care should be taken in the dose selection and regular renal function be monitored.

Undesirable effects

Gastrointestinal disturbances : Nausea, diarrhoea, gastric pain, constipation, vomiting, metallic taste in mouth. These reactions are generally dose related and disappear when the dose is reduced.

Dermatological effects : Rash, puritus, urticaria, erythema & flushing.

Miscellaneous: Headache and dizziness.

Hypoglyacemia: Glimepiride appears to be associated with a low incidence of hypoglycaemia. Glimepiride may have the potiential to produce adverse cardiovascular effects, however glimepiride has been established agent for the treatment of type 2 diabetes for a number of years without adverse cardiovascular effects.

Overdosage

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as medical emergency, requiring immediate hospitalization. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 ml of concentrated glucose solution (20 to 30 %). This must be followed by the infusion of more dilute glucose solution (10 %) at a rate that will maintain blood glucose levels above 1g/L. Patients should be monitored closely and, depending on the patients condition after this time, the doctor will decide if further monitoring is necessary. Dialysis is not beneficial to patient due to strong binding of glimepiride to plasma proteins.

Overdosage of sulphonylureas, including glimepiride, can produce hypoglycaemia. Mild hypoglycaemic 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.

Lactic acidosis is a rare, but serious, metabolic complication that can occur if metformin accumulates during treatment due to overdosing. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.

Stimulating the release of insulin from functioning pancreatic beta cells

Metformin improves glucose tolerance in patients with type 2 diabetes (NIDDM),

lowering both basal and postprandial plasma glucose.

Metformin decreases hepatic glucose production,

decreases intestinal absorption of glucose

improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Toralip-10 Tablets

Atorvastatin 10 mg