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COMPOSICIÓN


Each tablet contains :


Metformin Hydrochloride …..............…. 850 mg
Excipients c.s.p. ...................................... 1 tableta

INDICATIONS :

Metformin is used to treat patients with type 2 diabetes to control hyperglycemia that cannot be controlled with diet, exercise, weight reduction or when insulin therapy is not required nor feasible. It is used as monotherapy or together with sulfonylureas or insulin when they fail to provide adequate glycemic control individually.

In the event of a primary or secondary failure of the therapy with sulfonylureas alone, caution should be taken when combining Metformin with high doses of sulfonylureas in the treatment of non-obese patients with type 2 diabetes who have not responded to sulfonylureas; hence, insulin may be the preferred treatment in these cases. Metformin is also indicated for the treatment of polycystic ovary syndrome.
 

PHARMACOLOGICAL ACTION :

Metformin is an anti-hyperglycemic agent that potentiates the effect of insulin by mechanisms not yet fully understood. Metformin does not stimulate pancreatic beta cells to increase insulin secretion. The secretion of insulin must be present for Metformin to work effectively. It appears that Metformin decreases hepatic glucose production and improves insulin sensitivity by increasing uptake and peripheral glucose use.

It is known that Metformin may increase the number and / or affinity of insulin receptors on the surface of cells membrane, especially in peripheral receptor sites, and promotes the correction of a decline in the regulation of insulin receptors. This effect increases the sensitivity to insulin in receptor binding and post receptor sites, and increases glucose uptake peripherally. Insulin concentration remains unchanged or slightly reduced while improving glucose metabolism. At therapeutic dose, Metformin does not cause hypoglycemia in diabetic and nondiabetic patients. In addition, the metabolic effects of Metformin increase the reserve of hepatic glycogen in diabetic patients, but not in nondiabetic patients. It reduces the oxidation of fatty acids and the formation of acetyl coenzyme A, and may decrease the absorption of glucose in the intestine.

The uptake of glucose and free fatty acid oxidation are effects whose causes are considered as mediate non-insulin mechanisms.

CONTRAINDICATIONS :


The following contraindications have been selected on the basis of their potential clinical relevance and are not necessarily inclusive. With the exception of special circumstances, this medication should not be used when the following medical problems exist : Any condition that requires careful control of blood glucose, such as severe burns, dehydration, diabetic coma, diabetic ketoacidosis, hyperosmolar nonketotic coma, severe infection, major surgery, severe trauma (the risk of side effects related to uncontrolled blood glucose or lactic acidosis may be increased). Conditions associated with hypoxemia such as cardiorespiratory failure; cardiovascular collapse; congestive heart failure; acute myocardial infarction; acute, severe, or chronic liver disease; history of active lactic acidosis; renal dysfunction or history of kidney disease. Lactic acidosis is associated with these conditions and the risk is increased when Metformin is used concurrently.

Metformin should be suspended for 48 hours in patients undergoing radiologic studies such as angiography, intravenous cholangiography, computed tomography (CT); pyelography, urography, which involve intravascular administration of iodinated contrast materials, as contrast dye may temporarily cause functional oliguria, which might lead to lactic acidosis. Metformin should not be restarted until after the normalization of kidney function.

Hypersensitivity to Metformin.

When the following medical problems exist, the risk-benefit should be taken into consideration :

Diarrhea; gastroparesis; intestinal obstruction; vomiting; or other conditions that slow food absorption (conditions that decrease or delay stomach emptying may require altering the dose of Metformin or replacement to insulin). Hyperglycemia-causing conditions such as female hormone changes; high fever; hypercortisolism not responding to treatment; psychological stress (by increasing blood glucose, these conditions may elevate the need for more frequent monitoring of glucose, thus, raise the need for a temporary or permanent increase in the dose of Metformin, or replacement to insulin if blood glucose is not controlled).

Uncontrolled Hyperthyroidism, (Hyperthyroidism aggravates diabetes mellitus by increasing plasma concentration and absorption of glucose, as well as decreased glucose tolerance).

Hypoglycemia-causing conditions such as adrenal insufficiency, weak physical condition, malnutrition, uncontrolled pituitary insufficiency (these conditions, inherent to the predisposition of patients to the risk of developing hypoglycemia, increase their risk to develop severe hypoglycemia during treatment with Metformin, hence, an adjustment in dosage and close blood glucose monitoring may be required). Uncontrolled Hypothyroidism (this condition is associated with reduced absorption of glucose and altered lipoprotein and glucose metabolism; a lower dose of Metformin may be needed when Hypothyroid conditions exist. However, it may be required to initiate thyroid treatment at an increased dose of Metformin, since glucose control may be difficult while the patient is euthyroid).


DRUG INTERACTIONS :

The following interactions and / or related problems have been selected on the basis of their potential clinical relevance and are not necessarily inclusive. The concurrent administration of Metformin with any of the medications listed below, depending on the amount taken, may interact with Metformin. The administration of any drug that may affect the metabolic or glycemic control of diabetes mellitus requires careful monitoring of blood glucose concentration by either the patient or a health professional. This is particularly important when adding or removing a drug from an established treatment regimen, and may require adjustments in diet or antidiabetic agent dosage or both, which may vary depending on the severity of the illness.

Excessive or chronic alcohol intake (combined use of alcohol and Metformin may elevate blood lactate concentration, thus leading to lactic acidosis; it may also increase the risk of developing hypoglycemia, especially when alcohol is ingested without food).

Cimetidine or other cationic drugs excreted by renal tubular transport such as Amiloride; blocking agents of calcium channel blockers, especially Nifedipine; Digoxin; Morphine; Procainamide; Quinidine; Quinine; Ranitidine; Triamterene; Trimethoprim; Vancomycin. Cimetidine inhibits renal tubular secretion of Metformin, reducing renal clearance of this drug for up to 27% in 24 hours, which may significantly increase its peak plasma concentrations by approximately 60% for 6 hours; hence, dosage adjustment may be required. (In a single-dose study, the administration of Nifedipine concomitantly with Metformin enhanced the absorption of Metformin by 9% in the area under the plasma concentration versus time curve (AUC), and 20% in the peak plasma concentration; while urinary excretion and half-life remained the same.) Its clinical relevance, and whether similar effects are produced by other calcium blocking agents, is unknown. (Other cationic medications excreted by renal tubular transport have the potential to increase the peak plasma concentration or interfere with renal clearance of Metformin. Careful monitoring of blood glucose is strongly recommended when these medications are given concurrently with Metformin). Furosemide (in a single-dose study in healthy volunteers, administration of Furosemide concomitantly with Metformin increased AUC of Metformin by 15%, while renal clearance was not affected. Its clinical relevance is unknown, however, decreasing the dose of Metformin may be required).

Drugs that may cause hyperglycemia such as : oral contraceptives containing estrogen; corticosteroids; thiazide diuretics; estrogens; isoniazid; niacin; phenothiazines, especially Clorpomazine; phenytoin; sympathomimetics; thyroid hormones (these can contribute to hyperglycemia, an increase in the dose of Metformin or its replacement by another antidiabetic agent may be required). Drugs that may cause hypoglycemia such as : clofibrate; monoamine oxidase (MAO) inhibitors; Probenecid; Propanolol; Rifabutin; Rifampicin; Salicylates; extended-release Sulfonamides; Sulfonylureas. (These drugs may cause hypoglycemia, thus, reducing the dose of Metformin may be required. Although no studies have been conducted on the concurrently administration of many of these agents with Metformin, it is expected that drugs with high bond to proteins when used concurrently with Metformin cause fewer problems than when they are used in conjunction with sulfonylurea antidiabetics).


PRECAUTIONS :

Carcinogenicity : Studies in rats and mice for a period of 104 and 91 weeks, respectively, at doses approximately three times the recommended daily human dose, showed no evidence of carcinogenicity.
Tumorigenicity : There was no tumorigenicity observed in male rats, however, female rats had an increased incidence of benign stromal uterine polyps.
Mutagenicity : Tests have not found Metformin to be mutagenic.
Fertility : No problems have been documented in humans. Furthermore, no impaired fertility in male or female rats have been reported after administration of twice the recommended daily human dose.
Pregnancy : (Pregnancy Category B according to theFDA.) There have been no adequate and well-controlled studies in pregnant women with the use of antidiabetics. Therefore, it is recommended to maintain healthy blood glucose levels with diet alone or in combination with insulin during pregnancy, and the use of all oral antidiabetic agents is discouraged. The administration of insulin instead of Metformin for the treatment of type 2 diabetes and gestational diabetes mellitus (GDM) allows maintenance of blood glucose concentrations very close to normal. Elevated blood glucose levels have been associated with a high incidence of major congenital abnormalities in early pregnancy (5-8 weeks), and high perinatal morbidity and mortality later in pregnancy
Breastfeeding : Studies in lactating rats show that Metformin is excreted into milk. However, no problems have been documented in humans.
Pediatric and Adolescent Use : No information is available regarding the relationship between the age of these patients and the effects of this drug. Safety and effectiveness of Metformin in pediatric and adolescent patients have not been established yet.

Geriatrics : Clinical studies have not demonstrated geriatric-specific problems that may limit the use of Metformin in elderly patients. However, due to possible gastrointestinal intolerance, it is recommended to start treatment with low doses to be adjusted gradually according to renal clearance; but the maximum dose should not be used. Because of their age, geriatric patients are more prone to renal dysfunction or peripheral vascular disease, therefore, dose adjustment or discontinuation of treatment may be required.

SIDE EFFECTS :

The following side effects have been selected on the basis of their potential clinical relevance which are not necessarily inclusive.
Those that require medical attention :
Rare : Megaloblastic anemia (fatigue / weakness); hypoglycemia (anxiety; odd behavior (similar to drunkenness), blurred vision, cold sweats, confusion); and lactic acidosis (diarrhea, restlessness, muscle pain and cramping, unusual drowsiness, fatigue and weakness).

Note : Hypoglycemia is not a common side effect in treatments with Metformin, unless there are conditions or factors that may trigger it, such as fasting, concurrent use with other antidiabetic agents, or toxic doses of Metformin. It is reported that the concurrent use of Metformin with sulfonylureas reduces basal glucose concentrations by approximately 20% than with the administration of sulfonylurea alone. Reported cases of lactic acidosis, a potentially fatal complication, have occurred when a contraindication existed; otherwise, the risk with the use of Metformin is minimal. Patients did not show symptoms of lactic acidosis, however, presented acute symptoms of other problems that resulted in the accumulation of Metformin due to poor kidney function or failure in conditions such as myocardial infarction or kidney or liver disease.

Those that require medical attention, only if symptoms persist or are bothersome :

Common :
Anorexia, diarrhea, dyspepsia, flatulence, headache, metallic taste, nausea, vomiting, weight loss.

Note : Diarrhea, dyspepsia and nausea occur less frequently when small doses are used initially, and headache and metallic taste are transient. If diarrhea occurs after several months of treatment with Metformin, it might be a symptom of lactic acidosis and the patient should consult his / her physician immediately.


WARNINGS :

• Adherance to treatment, including not taking more nor less medication than prescribed.
• Visit your doctor regularly to check the progress of your treatment.
• Hypersensitivity to Metformin.
• Adequate dosing : A missed dose should be taken as soon as possible, but do not take it if it is almost time for the next dose. Do not double the dose.
• Take with food.
• Do not drink alcohol while taking this medication.
• Do not take other medicines without consulting a doctor.
• Recognize the symptoms of lactic acidosis such as diarrhea, restlessness, severe muscle pain or cramping, unusual drowsiness, unusual fatigue and weakness.
• If symptoms of lactic acidosis occur, control blood glucose and immediately seek medical attention.
• Consult your doctor if vomiting occurs.
• Recognize the symptoms of hypoglycemia, hyperglycemia and ketoacidosis, and immediately seek medical asssistance.


TREATMENTS IN CASE OF OVERDOSE :

Treatment of lactic acidosis :

Few cases of Metformin-induced lactic acidosis have been reported. Hemodialysis with sodium bicarbonate has been used despite the limited information available about its effectiveness. Peritoneal dialysis has also been used, however, hemodialysis is the preferred method in cases in which dialysis is needed, such as in patients with shock syndrome. Metformin is eliminated quickly through the kidneys, dialysis may not be necessary after renal function is restored. Dialysis solutions, containing lactate as a buffering agent, should not be taken concomitantly in cases of Metformin-induced lactic acidosis.

Treatment of mild to moderate hypoglycemia :


The treatment of mild hypoglycemia involves the rapid ingestion of a source of easily absorbed sugar, such as glucose tablets or gel, fruit juice, corn syrup, regular soda, honey, sugar cubes or granulated sugar (dissolved in water); followed by a blood glucose check. (A full glass of orange juice with 2 or 3 heaping teaspoons of sugar is frequently used as a source of glucose.)
Check blood glucose again in 15 minutes.
Get immediate medical assistance.
It may be necessary to adjust the dosage of Metformin.
It may be necessary to adjust the nutrition pattern, as well.

Treatment of acute overdose or severe hypoglycemia, including coma :

Note : The administration of dextrose is the mainstay in the treatment of hypoglycemia, but, the sudden exposure to hyperglycemia caused by a rapid injection of hypertonic dextrose, may stimulate the pancreas, eager for sulfonylurea, when sulfonylureas are used concurrently with Metformin for an increased insulin release, thus worsening the hypoglycemia.

In the event of severe hypoglycemia seek medical attention immediately. Promptly inject 50mL of 50% glucose intravenously to stabilize the patient. Afterwards, administer a continuous infusion of injectable 5 to 10% dextrose to maintain a mild hyperglycemia (approximately a concentration of 100mg/dL [5.55 mmol / L] blood glucose) for up to 12 days. Intravenous dextrose therapy should not be discontinued suddenly. Do not rely on the administration of glucose by mouth to maintain a euglycemia, because 60% of oral doses of dextrose are stored as hepatic glycogen with only 15% remainder used by the brain and another 15% by insulin-dependent tissues.
Glucagon (1-2 mg), administered intramuscularly, is useful to initiate a quick mobilization of hepatic glucose stores, but it may be ineffective if glycogen stores are depleted; therefore, it should be used after the administration of dextrose.

Diazoxide (200 mg orally every 4 hours, or 300 mg intravenously for a period of 30 minutes every 4 hours) may be used in patients not responding to therapy with dextrose alone, or patients in coma, as an aid to the infusion of dextrose in the treatment of hypoglycemia, afterwards, sodium concentration and hypotension should be monitored in patients.

Emesis may be induced with ipecac syrup if the overdose of Metformin has been produced in the last 30 minutes and if the patient is alert, with intact reflex to throw up (vomit) without numbness or seizures. Otherwise, gastric lavage (after endotracheal entubation) will be necessary.

Gastric decontamination by the administration of repeated doses of oral activated charcoal with a cathartic, but its usefulness has not been established yet.
Monitor vital signs, arterial blood gases, blood glucose and serum electrolytes (especially calcium, potassium and sodium) as indicated. Initially, blood glucose concentrations should be monitored as often as every 1-3 hours. Blood urea nitrogen and serum creatinine must also be monitored.

Cerebral edema should be treated with mannitol and dexamethasone.

Hypokalemia, should be treated with potassium supplements.

Patient should be admitted into a hospital for a period of 6 to 91 hours (an average of 24 hours), because hypoglycemia may be recurrent and prolonged. Other supportive measures should also be used as indicated.


DOSE AND ROUTES OF ADMINISTRATION :

Usual adult dose (antihyperglycemic agent) :
As monotherapy :
Initial : 500 mg taken orally twice daily, taken with food in the morning and night. The daily dose can be increased by 500 mg at weekly intervals as directed. An alternative dose is 850 mg daily taken with food in the morning. The daily dose can be increased by 850 mg in 14-day intervals.
Maintenance : 500 or 850 mg taken orally two or three times a day with food.
In combination with a sulfonylurea : The dose of each agent should be adjusted to achieve the desired level of glycemic control.
In combination with insulin : 500 mg a day taken orally, initially. The dose may be increased by 500 mg in weekly intervals as directed.

Note : The prevalent insulin dose must be maintained after the initiation of the therapy with Metformin. However, the insulin dose should be reduced by 10-25% when the concentration in fasting plasma glucose decreases to less than 120 mg per dL (6.7 mmol per L).
Maximum adult dose : 2550mg per day.

Usual pediatric dose (antihyperglycemic agent) :

Children up to 10 years of age : Its safety and efficacy has not been established.

Children older than 10 years of age :
Initial : 500 mg twice daily taken orally with food. The daily dose can be increased by 500 mg weekly up to 2000 mg per day in divided doses.

Maximum pediatric dose : 2000 mg per day.

Usual geriatric dose :

Some sensitive patients may require an initial dose reduction. The maximum adult dose is not recommended in geriatric patients.

Polycystic Ovary Syndrome :

Initial : 500 mg twice daily taken orally with food.
Maintenance : 500 mg three times daily or 850 mg twice daily.

PRESENTATION :

GLUCOFINN :

Pack containing 2 coated tablets (in blister).
Pack containing 4 coated tablets (in blister).
Boxes of 20; 32; 48; 80; and 100 coated tablets (in blisters).

STORAGE :

Store at 15-30 ºC protected from light. Keep away from the reach of children.

“ALWAYS CONSULT YOUR DOCTOR”

MASTER FARMA S.A.

Address:

Calle Mariano Odicio 490,
Miraflores,
Lima 18 - Perú

Phone:
+51 (1) 446 1250     
+51 (1) 242 5577

Fax:

+51 (1) 445 7701


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