WALFORMIN

COMPOSITION
Each uncoated Tablet contains :
Gliclazide B.P. ………. 80mg
Metformin Hydrochloride I.P. ……….. 500mg

Chemistry
Walformin tablet contains Gliclazide and Metformin Hydrochloride. Gliclazide, chemically is 1-(3-azabicycll [3.3.0.]Oct-3-yl)-3-p-tolylsulphonylurea. Metformin Hydrochloride is 1, 1-dimethyl biguanide hydrochloride.

Description
Walformin is a white, oblong, biconvex scored tablet. Walformin is our quality brand of combination of Gliclazide with Metformin containing Gliclazide 80mg and Metformin 500mg. Walformin is indicated for the treatment of Non-Insulin Dependent Diabetes Mellitus.

Clinical Pharmacology
Gliclazide is a second generation sulphonylurea which acts via stimulating beta cells of the islet of Langerhans of pancreas to release insulin. Gliclazide also enhances peripheral insulin sensitivity. Metformin enhance peripheral glucose uptake by the tissues and its utilisation. It also reduces hepatic glucose production. Metformin diminished insulin resistance.

There are reports in which combination treatment of sulphonylurea with metformin has shown to achieve satisfactory control of blood sugar levels for several years, than either agent used alone. Such combination has been reported to be quite useful in comparative studies where secondary failure to sulphonylureas has occurred. The combination provides an additional glycaemic control (shown to lower blood glucose by 20%) and thus obviate the need for insulin in some patients.

Gliclazide has less propensity to cause hypoglycaemia and weight increase unlike other sulphonylureas. Gliclazide promptly induces the first phase of insulin release as is not commonly observed with Glibenclamide, as well the second phase of insulin release is well maintained. Thus the necessary insulin is released in response to meal intake.

Further, Gliclazide significantly has shown to reduce the micro- and macro-vascular complications. This can be attributed to its action in improving peripheral utilization of glucose, reducing insulin resistance and thus hyperinsulinaemia which contributes to positive influence on the lipid metabolism. This ultimately results in reduction of oxidative stress on LDL, Free fatty acids and deposition of cholestrol in the the small or larger blood vessels.

Unlike other sulphonylurea's, Gliclazide has beneficial effect in reducing platelet aggregation as well as mild increase in levels of tissue plasminogen activator (in patients with DM, levels of TPA are found to be suppressed). By improving TPA levels, Gliclazide improves microcirculation since the tendency of clot formation is hampered and there is clot lysis.

Metformin enhances peripheral glucose uptake by the tissue and its utilisation. Metformin also reduces hepatic glucose production. Metformin in certain studies has also shown to reduce intestinal absorption of carbohydrates which at the moment appears to be insignificant in contributing to its anti diabetic action. It is less likely to cause lactic acidosis, unlike its counter part i.e. Phenformin. Metformin has favourable effect on the lipid metabolism. It has also shown to reduce blood fibrinogen levels, thus minimising intra vascular coagulation. It produces cholesterol uptake by the arteries and also reduces platelet adhesiveness, which contributes to the protection from intravascular coagulation. In obese diabetics it promotes weight loss. Thus besides being antidiabetic, it also exerts cardio-protective effects.

Pharmacokinetics
Single oral dose of gliclazide, 40 to 120mg results in a Cmax of 2.2 to 8mg/1 within 2 to 8 hours. Steady state concentrations are achieved after 2 days of administration of 40-120mg of gliclazide. Administration of gliclazide with food reduces Cmax and delays Tmax. The volume of distribution is low due to extensive protein binding (85-97%). The half life of gliclazide varies from 8.1 - 20.5 hours after single dose administration. Gliclazide is extensively metabolised to 7 metabolites predominantly excreted in the urine, the most abundant being the carboxylic acid derivative : 60-70% of the dose is excreted in the urine and 10-20% in the faeces. Metformin has absolute oral bioavailability of 50-60%. GIT absorption is complete within 6 hrs of ingestion.

Rationality
Sulphonylureas and biguanides although have a different mode of action but this is complementary and supplementary producing an additive effect on lowering the blood glucose levels. This is achieved at no extra risk of adverse effects of their pharmacological class.

Gliclazide acts via stimulating beta cells of the islet of Langerhans of pancreas to release insulin. Gliclazide also enhances peripheral insulin sensitivity. Metformin enhances peripheral glucose uptake by the tissues and its utilisation. It also reduces hepatic glucose production. Metformin diminishes insulin resistance.

There are reports in which combination treatment of sulphonylurea with metformin has shown to achieve satisfactory control of blood sugar levels for several years, than other agents when used alone. Such combination has been reported to be quite useful in comparative studies where secondary failure to sulphonylureas has occurred. Thus the combination provides an additional glycaemic control (shown to lower blood glucose by 20%) and thus obviate the need for insulin in some patients.

Gliclazide has less propensity to cause hypoglycaemia and weight increase unlike other sulphonylureas. Further, metformin is associated with improving peripheral resistance and other peripheral actions without any effect on insulin released, hence, it does not cause weight gain.

Gliclazide has shown to reduce both macro and micro-vascular complications which may be associated with hyperglycaemia, hyperinsulinaemia, hyperlipidaemia with a possible association of hypertension. Metformin has clearly demonstrated a reduction in the fasting and post-meal plasma levels of insulin and triglycerides, increase in HDL cholesterol, increase in tissue plasminogen activators, decrease in platelet adhesiveness. The two drugs i.e. metformin and gliclazide appear to be pharmacokinetically compatible since metformin is not bound to plasma protein and does not get metabolised in the liver, so interaction with gliclazide (which is highly protein bound - 80-90% and metabolised in the liver is a very rare possibility).

Thus the combination of gliclazide and metformin would be beneficial in treatment of Type II diabetes mellitus patients who do not respond to single agent alone along with diet restrictions and exercise. Moreover, the combination will also reduce the associated macro and micro-vascular complications.

Indications
Walformin is indicated for Type II Diabetes Mellitus (NIDDM) in adults, with or without obesity, not responding to diet restriction and exercise.

Contraindications
Insulin-dependent diabetes mellitus, renal or hepatic failure, alcoholism, NIDDM complicated by severe ketosis and acidosis, diabetic pre-coma and coma, patients undergoing surgery, after-severe trauma or during infections, chronic obstructive pulmonary disease, coronary heart disease, cardiac failure, peripheral vascular disease, pregnancy, known hypersensitivity to any of the ingredients.

Warnings
Hypoglycaemia may occur if the patient's dietary intake is reduced or after accidental or deliberate overdose or after severe exercise, trauma and stress. Hypoglycaemic symptoms can be reduced by prescribing a diabetic meal plan. Immediate intervention should be done if signs and symptoms of hypoglycaemia occur.

Precautions
Adjust dose of combination according to blood and urinary glucose levels during the first few months. However, there have been few reports of lactic acidosis in patients of renal or liver disease.
Usage in pregnancy - Contraindicated.
Paediatric use - Safety and effectiveness in children have not been established.

Drug Interactions
Diuretics, barbiturates, phenytoin, rifampicin, corticosteroids, estrogens, estroprogestogens and pure progestogens may reduce the glycaemic control. Its hypoglycaemic action may be potentiated by salicylates, phenylbutazone, sulphonamides, beta-blockers, clofibric acid, vitamin k antagonist, allopurinol, theophylline, caffeine and monoamine oxidase inhibitors. Concomitant administration of gliclazide with agents that increase blood glucose levels should not be considered without careful monitoring of blood glucose levels to avoid hyperglycaemia. Acarbose and guar gum has been shown to decrease the oral bioavailability of metformin significantly.

Adverse reactions
Gastrointestinal disturbances -
Nausea, diarrhoea, gastric pain, constipation, vomiting, metallic taste in mouth.
Dermatological effects -
Rash, pruritus, urticaria, erythema and flushing.
Miscellaneous -
Headache and dizziness.

Gliclazide appears to be associated with a low incidence of hypoglycaemia. Gliclazide may have the potential to produce adverse cardiovascular effects, however gliclazide has been an established agent for the treatment of NIDDM for a number of years without adverse cardiovascular effects. Impaired gastrointestinal absorption of vitamin B12 and folic acid has been associated with long term metformin therapy. Overdosage and Treatment Hypoglycaemia may occur in case of an overdosage. In the event of an overdosage, gastric lavage should be performed and correction of hypoglycaemia should be attempted by intravenous administration of hypertonic glucose (10 or 30%) with continued monitoring of the patient's blood glucose levels. Dosage and Administration 1-2 Walaphage Plus tablets once or twice daily with meals to a maximum of 4 tablets/day. The advantages offered by Walformin over other combinations of sulphonylurea and metformin.

Walformin Other combinations
Pharmacokinetics Pharmacokinetically compatible combination since both can be administered just before the meals Other combinations - Glipizide and Metformin - Glipizide is necessary to be given 1/2 an hour before the meals whereas Metformin is just before or along with the meals. Hence, this is pharmacokinetically not compatible combination.

Clinical trials Gives reduction in glycosylated haemoglobin levels. Combination well tolerated and reported to be as efficacious as the existing Glibenclamide Metformin combination. Increased possibility of adverse reactions noted.

Secondary failure a) Exhibits anti platelet activity.
b) Increased fibrinolytic activity.
c) Reduces micro- vascular complications No such effects reported with other sulphonylureas.
a) No fibrinolytic effect
b) No such effect noted.
Haematological adverse effects a) No haematological adverse effects a) Haematological reactions for other sulphonylureas noted in the form of leucopenia, thrombocytopenia, aplastic anaemia, agranulocytosis, haemolytic anaemia and pancytopenia.
Weight gain Less weight gain with Gliclazide More chances of weight gain with other sulphonylureas.


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