Pharmacotherapeutic group: Blood glucose lowering drugs.

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.

Metformin may act via 3 mechanisms:

-Reduction of hepatic glucose by inhibiting the new sugar and glycogenolysis.

-In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.

-Delay of intestinal glucose absorption.

 

After an oral dose of metformin, maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the recommended metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown

Distribution:
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 l.

Metabolism:
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:
Renal clearance of metformin is> 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Paediatric population
Single dose study: After single doses of metformin hydrochloride 500 mg paediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.
Multiple dose study: After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

 

Adult onset diabetes (Type II diabetes), particularly in obese patients, if dietary treatment and physical activity alone are not sufficient.

 

METFORMIN-ElSaad must not be used in these cases :

patients with impairments of renal or hepatic function.

severe lung diseases with impairment of pulmonary function.

severe functional impairment of the heart or circulatory system.

METFORMIN-ElSaad must particularly not be used in patients with decompensation of the glucose metabolism with or without unconsciousness, or with or without over acidification of the blood (acidotic metabolic decompensation precoma, hyperosmolar or ketoacidotic, coma diabeticum ).

METFORMIN-ElSaad must also not be used in patients with severe infections, operations with general anaesthetic, x-ray examinations with contrast media injected into a vessel, conditions with increased dissimilation processes (catabolic states), e.g. neoplastic disorders, slimming courses with less than 1000 kcal or 4200 kj per day.

Alcoholism: Drinking alcohol increase the risk of lactic acidosis and hypoglycemia so the consumption of alcohol should therefore be avoided during a therapy with METFORMIN-ElSaad.

Known hypersensitivity to Metformin, or with insulin-dependent diabetes mellitus (type I diabetes mellitus) and with complete collapse of endogenous insulin production in diabetes mellitus II.

METFORMIN-ElSaad must not be used in pregnancy or during the breast-feeding period.

If x-ray examination with administration of contrast media into a blood vessel, or an operation with general anaesthetic is planned, treatment with METFORMIN-ElSaad must be interrupted 2 days before hand and not recommended until 2 days after the procedure.

 

Gastro-intestinal complaints such as anorexia, nausea, vomiting, abdominal pains and diarrhea may occur at the beginning of therapy. These complaints can be reduced by gradual dosage and taking the tablets with meals. Discontinuation of therapy is generally not necessary in the case of gastro-intestinal complaints, as they usually disappear, even if the dosage remains unchanged.

Patients may experience taste disturbance and there maybe weight loss .

Hypersensitivity reactions of the skin are very rare.

Very rarely, megaloblastic anemia may occur through inhibition of the absorption of vitamin B12 in the intestines.

Very rarely, metformin can assist the development of severe over acidification of the blood through lactic acid (lactate acidosis). Over acidification of the blood through lactic acid is manifested by nausea, vomiting, diarrhea, abdominal pains and exhaustion. Lactic acidosis can cause muscle pains, increased breathing rate, clouding of consciousness, and unconsciousness. Should you notice any complaints of this type, contact a doctor immediately.

 

 

-Other drugs can increase as well as decrease the effect of metformin hydrochloride. Tell the doctor which other drugs you are taking.

-Concomitant use not recommended with alcohol and iodinated contrast agents.

- Certain drugs may potentiate the effect of metformin, particularly sulfonylurea type of drug, this could produce a hypoglycemic reaction concomitantly. these drugs can be: long-acting sulfonamides, tubercolostatics, phenylbutazone, clofibrate, monoamine oxidase inhibitors, salicylates, probenecid and propranolol that lead to potentiate the effect of sulfonylurea  .

The co-administration of metformin and glyburide leads to decrease in glyburide AUC and Cmax.

In a single-dose study, metformin with furosemide, furosemide increased the metformin plasma and blood Cmax, but no information is available about the interaction of metformin and furosemide when coadministered chronically.

Nifedipine appears to enhance the absorption of metformin.

This group includes drugs like (amiloride, digoxin, morphine, procainamide, quinidine, quinine,

ranitidine, triamterene, trimethoprim, and vancomycin) are eliminated by renal tubular secretion.

Careful patient monitoring and dose adjustment of metformin or the interfering drug is recommended in patients who are taking cationic medications that are excreted via renal tubular secretion.

Other drugs tend to produce hyperglycemia and may lead to a loss of blood sugar control.

These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, estrogen plus progestogen, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid, and beta-2-agonists.

ACE-inhibitors may decrease the blood glucose levels. When such drugs are administered

to patients receiving metformin, the patient should be closely observed to maintain adequate glycemic control.

Patients receiving phenprocoumon or other antivitamin K anticoagulants should be monitored carefully when

both types of drugs used simultaneously. In such cases, an important increase of prothrombin time may occur upon cessation of metformin therapy, with an increased risk of hemorrhage.

 

The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2 or 3 time daily given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements .

A slow increase of dose may improve gastrointestinal tolerability.

In patients receiving a high metformin hydrochloride dose (2 to 3 grams per day), it is possible to replace two metformin hydrochloride 500 mg film – coated tablets with one 1000 mg film-coated tablet.

The maximum recommended dose of Metformin hydrochloride is 3 g daily, taken as 3 divided doses.

If transfer from another oral antidiabetic medicinal product is intended: discontinue the other medicinal product and initiate metformin hydrochloride at the dose indicated above.

Combination with insulin:

Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of 500 mg or 850 mg 2 or 3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Due to potential for decreased renal function in elderly patients, the Metformin hydrochloride dosage should be adjusted based on renal function.

Monotherapy and combination with insulin:

-METFORMIN ELSaad 1000 can be used in children from 10 years of age and adolescents.

-The usual starting dose is 500 mg or 850 mg Metformin hydrochloride once daily, given during meals or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements .A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of Metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

 

Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.

 

METFORMIN-ElSaad 500- film-coated tablet

Pack of 20 F.C tablets in blister :Each film-coated tablet contains metformin hydrochloride 500 mg.

METFORMIN-ElSaad 850- film-coated tablet

Pack of 20 F.C tablets in blister :Each film-coated tablet contains metformin hydrochloride 850mg.

METFORMIN-ElSaad1000- film-coated tablet

Pack of 20 F.C tablets in blister:Each film-coated tablet contains metformin hydrochloride 1000mg.

 

Store METFORMIN-ElSaad - film-coated tablet at temperature between (15-30)oC protect from light.