Glyciphage, Metformin Patient Information Sheet

Generic Glucophage, Metformin Tablet

FORMULA :

Each uncoated extended release tablet contains:

Metformin Hydrochloride I.P. ………………….1000mg

Excipients q.s.

Type 2 Diabetes Mellitus is growing problem across the world. There is now strong evidence that intensive control of blood glucose can significantly reduce and retard the micro vascular complications of retinopathy, nephropathy and neuropathy. Ultimately however, up to 80% of Type 2 diabetes die from macro vascular cardiac disease. These increase incidences of atherosclerotic disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in Type 2 diabetes. There is strong evidence that insulin resistance is involved in the development of, not only hyperglycemia, but also dyslipidemia, hypertension, hypercaogulation, vasculopathy and ultimate atherosclerotic cardiovascular disease. This cluster of metabolic abnormalities has been termed as the insulin resistance or cardiovascular dysmetabolic syndrome.

Metformin is a biguanide and belongs to a class of drugs called "insulin sensitizers" and it exerts direct effect on the mechanisms of insulin resistance. These effects not only improve insulin sensitivity and glycemic control with reduced insulin requirements, but also have potentially favorable effects on other components of the cardiovascular dysmetabolic syndrome.

For better patient compliance Metformin is formulated in extended release form.

TECHNOLOGY OF GYCIPHAGE EXTENDED RELEASE

GLYCIPHAGE SR 1gm tablets comprise of a dual hydrophilic polymer matrix system. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage by process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up eventually by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the faces as a soft, hydrated mass.

CLINICAL PHARMACLOGY

MECHANISM OF ACTION

Decreasing hepatic gluconeogenesis is the primary therapeutic effect of Metformin in Type 2 Diabetes Mellitus. In addition, Metformin appears to improve utilization of glucose in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improve binding of insulin to the insulin receptors since Metformin is not effective in diabetes without some residual functioning pancreatic islet cells. Unlike the sulfonylureas, Metformin rarely causes hypoglycemia since it does not significantly change insulin concentrations. An important distinction is that sulfonylureas increase insulin secretion thus making them useful in non-obese Patients with Type 2 Diabetes Mellitus, while Metformin improves insulin resistance, which is a common pathophysiologic finding in obese patients with Type 2 Diabetes Mellitus.

Clinically, Metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25-30%. Metformin does cause weight gain and in fact, may cause a modest weight loss due to drug induce anorexia. Metformin also decreases plasma VLDL triglycerides resulting in a modest decrease in plasma triglycerides and total cholesterol. Patients receiving Metformin show a significant improvement in hemoglobin AUC and a tendency towards improvement in the lipid profile, especially when baseline values are abnormally elevated.

PHARMACOKINETICS

Following a single oral dose of GLYCIPHAGE SR 1gm tablets, maximum concentration is achieved with a median value of 7 hours(range: 4-8 hrs.), peak plasma levels approximately 20% lower versus the same dose of immediate release Metformin. With the GLYCIPHAGE SR 1gm the extent of Metformin absorbed is increased by 50% when given with food, but Cmax and Tmax are unaltered, thus the extended release tablet may also be taken with food. Metformin is distributed rapidly into peripheral body tissues and fluids and appears to distribute slowly into erythrocytes and to the deep tissue compartment (most likely GI tissues). The highest concentrations of Metformin are found in GI tract (10 times the concentrations in the plasma) and lower concentration in the kidney, liver and salivary gland tissue. Metformin does not bind the hepatic or plasma proteins. The liver does not metabolize Metformin and hence the risk of lactic acidosis is must less (than for phenformin).

The drug is excreted unchanged by the kidneys, through an active tubular process. The plasma elimination half life is roughly 6.2 hrs. in patients with normal renal function. In blood, the elimination half-life is approximately 17.6 hrs., suggesting that the drug may be distributing into the RBC's.

INDICATIONS:

• Monotheraphy for adults (above 17 yrs.) with Type 2 Diabetes Mellitus, where balanced diet, weight control and exercise have failed to control blood sugar levels.
• GLYCIPHAGE SR 1gm is especially useful if the patient is obese, as it helps to reduce weight. However, there is contraindication to the use of the drug in patients who are not overweight, as it helps to normalize weight and blood sugar levels rather than reduce it below normal.
• GLYCIPHAGE SR1gm may be added as a co prescription wit sulfonylureas and/or insulin, where the letter when given alone failed to control hyperglycemia.
• In IGT
• In PCOS
• IN essential hypertension

DOSAGE

• For the treatment of Type 2 (non-insulin dependent, NIDDM) Diabetes Mellitus uncontrolled by the diet alone:

For monotheraphy: Oral dosage- Adults: Initially, 500mg once daily with the evening meal. Increase in increments of 500 mg weekly, as needed, up to a maximum of 2000mg once daily, a trial of GLYCIPHAGE 1gm tablet twice daily should be considered. If doses of more than 2000mg per day are required, change to the appropriate dosage of immediate release Metformin tablet (GLYCIPHAGE) in divided doses.

Elderly or debilitated patients: Same as adult dosage: Avoid use if >80 years of age unless normal renal function is documented. In general, do not titrate to the maximum dose.

Adolescents & children : Safe and effective use has not been established.

• Switching to Metformin from other antidiabetic therapy:

Adults and elderly: when transferring from antidiabetic agents other than chlorpropamide, no transition period is required. When transferring from chlorpropamide, use caution during the first 2 weeks as there may be prolonged retention of chlorpropamide in the body.

• Addition of a sulfonylurea

Adults: The current insulin dose should be continued; initiate Metformin dose at 500 mg at the evening meal. For patients not responding adequately, the dose of Metformin may be increased by 500 mg after approximately 1 week thereafter until adequate glycemic control is achieved. The dose should not exceed 2000 mg/day. The insulin dose should usually be decreased by 10-25% when fasting plasma glucose decreases to less than 120mg/dl Individualize dosage of antidiabetic drugs as needed.

Elderly or debilitated patients: Avoid use if >80 years of age unless normal renal function is documented. In general, do not titrate to the maximum dose.

Adolescents and children : safe and effective use has not been established.

• Patients with hepatic impairment:

CrCl < 60 ml/min: Metformin use is contraindicated.

CONTRAINDICATIONS:

• Renal disease/dysfunction

(Serum creatinine level > 1.5 mg/dl) which may result from

-Cardiovascular shock

-Acute myocardial infarction

-Septicemia

• Congestive heart failure requiring pharmacological treatment
• Metabolic acidosis (acute/chronic)

- diabetic ketoacidosis

- lactic acidosis

Do not use Metformin in patients who have known Metformin hypersensitivity. Use Metformin with caution in the elderly. Metformin is substantially excreted by the kidney and the risk of adverse reactions is greater in patients with reduce renal function, care should be taken with dose selection and titration's.

Metformin is classified in FDA pregnancy risk category B, and is not recommended for use during pregnancy.

DRUG INTERACTIONS:

• 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, Proscainamide, Quinidine, ranitidine or Vancomycin) may decrease Metformin elimination by competing for common renal tubular transport systems. Hence, careful patients monitoring and dose adjustment of Metformin and/or interfering cationic drug is recommended.
• Metformin may result in suboptimal oral Vitamin B12 absorption by competitively blocking the calcium dependent binding of the intrinsic factor- Vitamin B12 complex to its receptor. The reaction very rarely results in pernicious anemia that is reversible with discontinuation of Metformin or with Vitamin B 12 supplementation.

• Nifedepine enhances the absorption of Metformin in it increases plasma Metformin (maximum by 20% and increases the amount of Metformin excreted in the urine).
• Concomitant administration of Captopril or Enalapril increases sensitivity to insulin and hence dosage of the oral antidiabetic agent may need to be reduced.
• If salicylates are administered or discontinued in patients receiving oral antidiabetic agent, patients should be monitored for hyperglycemia or loss of blood glucose control.
• Interactions between thiazide diuretics and oral antidiabetic agents decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia, thus leading to a loss of diabetic control. Hence diabetic patients should be monitored closely.
• Patients receiving estrogens, progestins or oral contraceptives, phenytoin, quinolones should be closely monitored for loss of diabetic control when therapy is instituted or discontinued.

PRECUATIONS:

The kidneys excrete Metformin, hence regular monitoring of renal function is advised in all diabetic.

GLYCIPHAGE SR 1gm should be stopped 2-3 days before surgery or invasive investigations and restarted only after normal renal function has been regained.

GLYCIPHAGE SR 1gm should be avoided in conditions that may cause dehydration or in patients suffering from serious infections or trauma.

Patients on long term Metformin therapy should be checked yearly for signs of Vitamin B12 deficiency and frequently in those who have tendency of malabsorption, as Metformin reduces intestinal absorption of Vitamin B12 and Folic Acid, though cases are rare.

SPECIAL PRECAUTIONS:

Pregnancy : Use of Metformin is not advisable during pregnancy. However in case of PCOS where pregnancy has resulted due to Metformin therapy continued uses may be done after carefully weighing risk to benefits ratio.

Lactation : Adequate human safety data is not available.

Children : Not recommended for use in children.

ADVERSE REACTONS:

GLYCIPHAGE SR 1gm is usually well tolerated. The most common side effect is minor gastrointestinal disturbance, which is often self limiting or minimized by lowering the dose.

Lactic acidosis has occurred but is very rare, and is usually due to a specific contraindicated state rather than the drug. In patients with metabolic acidosis, even if there is no evidence of ketoacidosis as yet, GLYCIPHAGE SR 1 gm must be stopped and the condition treated as a medical emergency.

GLYCIPHAGE SR 1gm does not lower blood sugar levels in non-diabetics when used as a monotherapy.

PRESENTATION:

GLYCIPHAGE SR 1 gm tablets are available in blister pack of 10 Tablets, 10 such blister packs in a cartoon.

Manufactured and Marketed by:

FRANCO-INDIAN

PHARMACEUTICALS PVT. LTD.

20, Dr. E. Moses Road, Mumbai-400011.