composition:

  Each  modified-release tablet  contains 750mg  Metformin Hydrochloride (equivalent to 585mg metformin base)

. Each  modified-release tablet  contains 1000mg  Metformin Hydrochloride (equivalent to 780mg metformin base)  

MECHANISM OF ACTION:

Metformin is an antihyperglycemic agent which decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

PHARMACOKINETICS:

• Following a single oral dose of metformin hydrochloride modified -release, Cmax is achieved with a median value of 7 hours .
• Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.
• The elimination half-life is approximately 17.6 hours.

- the extent of metformin absorption (as measured by AUC) from the METFORMIN MR tablet increased by approximately 50% when given with food.

- steady state plasma concentrations are generally <1 μg/mL.

Special Populations                   

Renal Insufficiency: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.

Geriatrics: (metformin hydrochloride modified -release tablets) treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

INDICATIONS:

Metformin hydrochloride modified -release is indicated to improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS:

Metformin hydrochloride modified - release is contraindicated in patients with:

• Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥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.
• Known hypersensitivity to metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis  with or without coma. Diabetic ketoacidosis should be treated with insulin.
• Metformin MR should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials because use of such products may result in acute alteration of renal function.

DOSAGE AND ADMINISTRATION:

• Metformin MR should generally be given once daily with the evening meal.
• The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin MR, either when used as monotherapy or in combination with sulfonylurea or insulin.

- Metformin MR tablets must be swallowed whole and never crushed or chewed.

• In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.
• The usual starting dose of metformin hydrochloride modified -release tablets is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal.
• Safety and effectiveness of metformin MR in pediatric patients have not been established.
• When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
• If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin MR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin MR.
• Metformin MR therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose metformin MR should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2000 mg for metformin MR. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and  metformin MR.

SPECIFIC PATIENT POPULATIONS:

• Metformin MR are not recommended for use in pregnancy.
• Metformin MR is not recommended in pediatric patients (below the age of 17 years).
•  The initial and maintenance dosing of metformin MR should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin MR.
• Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.

PREGNANCY AND LACTATION:

• Pregnancy  :Category B , It should not be used during pregnancy unless clearly needed..
• Nursing Mothers: A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

ADVERSE EFFECT:

• Diarrhea,  Nausea/Vomiting, Flatulence, Asthenia, Indigestion, Abdominal Discomfort, Headache.

WARNING AND PRECAUTIONS:

• Radiologic studies involving the use of intravascular iodinated contrast materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore metformin MR should be temporarily discontinued at the time of or prior to the procedure.
• Hypoxic states:Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. The drug should be promptly discontinued.
• Surgical procedures: Therapy should be temporarily suspended for any surgical procedure.
• 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 MR.
• Vitamin B12 levels—a decrease to subnormal levels, possibly due to interference with B12 absorption .
• Before initiation of metformin hydrochloride modified- release therapy and at least annually thereafter, renal function should be assessed and verified as normal.
• Metformin hydrochloride modified- release should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
• If acidosis of either form occurs, metformin hydrochloride modified- release must be stopped immediately.
• Hypoglycemia does not occur in patients receiving metformin hydrochloride modified- release alone under usual circumstances of use.
• When a patient is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur, it may be necessary to withhold metformin MR and temporarily administer insulin.

DRUG INTERACTION:

• Glyburide: Coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.
• Furosemide: Furosemide increased the metformin Cmax by 22% and AUC by 15%, without any significant change in metformin renal clearance.
• Nifedipine: Coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine.
• Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion have the potential for interaction with metformin by competing for renal tubular transport systems.
• Other—Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

OVERDOSAGE &TREATMENT:

Hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.