Biguanides

Metformin (brand name Glucophage) is a biguanide. Biguanides lower blood glucose levels primarily by decreasing the amount of glucose produced by the liver. Metformin also helps to lower blood glucose levels by making muscle tissue more sensitive to insulin so glucose can be absorbed. It is usually taken two times a day. A side effect of metformin may be diarrhea, but this is improved when the drug is taken with food.

Product description

Most Important Information about Glucophage (Metformin)

Pharmacokinetics

Possible Side Effects

More information about Glucophage (Metformin):

Cancer Benefit for Diabetes Drug Glucophage

Kidney Fund concerned about Glucophage fatality risk

FDA approves new indication for Glucovance oral antidiabetic

To get more information about Glucophage: GLUCOPHAGE MEDICATION.

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The FDA has approved Glucovance, as an adjunct to diet and exercise, for use in combination with another class of antidiabetic agents known as thiazolidinediones (TZDs), when adequate glycemic control is not achieved with Glucovance and diet and exercise.

The new indication provides physicians with yet another Glucovance therapy option by offering the flexibility of adding a TZD when patients require additional blood sugar control.

“Glucovance works by treating the major problems associated with type 2 diabetes — the inability to release sufficient insulin and the inability to use it effectively,” said George Dailey, M.D., head of the Division of Diabetes and Endocrinology, Scripps Clinic. “This new indication for Glucovance is an important treatment option in the struggle to control type 2 diabetes.”

The new indication for Glucovance is based on results from a 24-week clinical study, which evaluated the effects of adding rosiglitazone (a member of the thiazolidinedione class of agents) or placebo to the therapy regimen of patients with type 2 diabetes not adequately controlled on current oral antidiabetic therapy (either monotherapy or combination therapy) who were first switched to Glucovance.

In the study, 42 percent of patients on Glucovance plus rosiglitazone achieved an A1C level of <7 percent, which is the treatment goal recommended by the American Diabetes Association (ADA).

Glucovance is a product that combines glyburide and Glucophage® (metformin HCl tablets) — two widely prescribed oral antidiabetic agents — in a single pill. In clinical studies, Glucovance showed significantly greater reductions in glucose levels than glyburide or metformin. Glucovance was originally approved by the FDA in August 2000 and more than 8 million prescriptions have been written for the product during the past two years.

Glucovance is not for everyone. In rare cases, Glucovance may cause lactic acidosis (build-up of lactic acid in the blood), which is serious and can be fatal in half the cases. This occurs mainly in people whose kidneys are not functioning properly. Patients should tell their doctor about their alcohol use because it can increase their risk. Patients should not take Glucovance if they: have kidney problems, are 80 or older (unless their kidneys have been tested), are taking medication for heart failure, are seriously dehydrated, have a serious infection, or if they have or have had liver disease.

Source: Bristol-Myers Squibb Company.

Product description

Most Important Information about Glucophage (Metformin)

Pharmacokinetics

Possible Side Effects

More information about Glucophage (Metformin):

Cancer Benefit for Diabetes Drug Glucophage

Kidney Fund concerned about Glucophage fatality risk

To buy GLUCOPHAGE click HERE: My Family Drugstore

Glucophage is a biguanide hypoglycaemic developed by Lipha (Merck KGaA) and licensed to Bristol-Myers Squibb for the U.S. The product helps the body use insulin and is among the most common drugs for the management of Type II diabetes.

According to a study published in the Journal of the American Medical Association (JAMA), the product can cause a rare side effect, lactic acidosis, a build-up of lactic acid in the blood that is fatal in about half of all cases.

Although the drug package insert warns of this side effect and states that Glucophage should not be used by patients who have kidney disease or those taking drugs for heart failure, the concern is that patients may have kidney disease and not know it.

Product description

Most Important Information about Glucophage (Metformin)

Pharmacokinetics

Possible Side Effects

More information about Glucophage (Metformin):

Cancer Benefit for Diabetes Drug Glucophage

FDA approves new indication for Glucovance oral antidiabetic

For more information look HERE: My Family Drugstore

Review Data
Research was carried out at the University of Dundee in Scotland and included an analysis of data from two large registries: the Diabetes Audit and Research in Tayside Study (DARTS) and MEdicine MOnitoring unit (MEMO).
DARTS included data from about 13,000 people with diabetes in Britain, while MEMO included all pharmacy-dispensed prescription records from England�s National Health Service. The findings by Alistair Emslie-Smith, MB, ChB, and colleagues, were briefly reported in the 4 June 2005 issue of the British Medical Journal.
The study reported that 983 people with type 2 diabetes were diagnosed with cancer within one year of being diagnosed with diabetes, and these cases were compared with data from 1,846 people with type 2 diabetes who did not have cancer.
An analysis of data revealed no factors to explain the difference in mortality rates due to cancer, except for taking Glucophage. Some potentially distinguishing factors that they examined included gender, age, severity or duration of diabetes, weight, smoking and cholesterol levels. Researchers noted an inverse relationship between Glucophage exposure and cancer mortality (i.e., – higher doses and longer use were associated with lower cancer risk), but they also noted a trend toward lower cancer mortality even among people who took only one dose of Glucophage.

Hypothesis or Proof?
The study findings, while provocative, are not considered conclusive. Bo Ahren, MD, PhD, a professor of clinical metabolic research at Lund University in Sweden, commented to MedPage Today that he remains unconvinced that Glucophage offers protection against cancer. “I�ve seen the data,” he said. “I believe the data, but it has to be confirmed.”
The group who analyzed the data agree – noting, for instance, that they have not yet linked taking Glucophage with prevention of a particular type of cancer. Similarly, they are unprepared to suggest that Glucophage could lower the risk of cancer in non-diabetics.
“It is too early to think it (Glucophage) will become mainstream for patients to prevent cancer, but we know it has a role in pre-diabetics,” Dr. Emslie-Smith commented to MedPage Today. “If long periods of [Glucophage] are shown beneficial, then maybe that will justify using it earlier in patients at high risk.”

Sources:
EASD: Cancer Benefit Seen for Popular Diabetes Drug,

MedPage Today, 12 September 2005.
Metformin and the reduced risk of cancer in diabetic patients, Evans JMM et al., British Medical Journal, volume 330, pages 1304-1305.

Product description

Most Important Information about Glucophage (Metformin)

Pharmacokinetics

Possible Side Effects

More information about Glucophage (Metformin):

Kidney Fund concerned about Glucophage fatality risk

FDA approves new indication for Glucovance oral antidiabetic

To buy GLUCOPHAGE click HERE: My Family Drugstore

• nausea, vomiting, abdominal pain, or diarrhea at the start of therapy;
• abdominal bloating or increased gas production; or
• decreased appetite or changes in taste (metallic taste in your mouth).

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Glucophage (Metformin)?

You may be more likely to have hyperglycemia (high blood sugar) if you are taking Glucophage with other drugs that raise blood sugar. Drugs that can raise blood sugar include:

• isoniazid;
• diuretics (water pills);
• steroids (prednisone and others);
• phenothiazines (Compazine and others);
• thyroid medicine (Synthroid and others);
• birth control pills and other hormones;
• seizure medicines (Dilantin and others); and
• diet pills, or medicines to treat asthma, colds or allergies.

You may be more likely to have hypoglycemia (low blood sugar) if you are taking Glucophage with other drugs that lower blood sugar. Drugs that can lower blood sugar include:

• some nonsteroidal anti-inflammatory drugs (NSAIDs);
• aspirin or other salicylates (including Pepto-Bismol);
• sulfa drugs (Bactrim and others);
• a monoamine oxidase inhibitor (MAOI);
• beta-blockers (Tenormin and others); or
• probenecid (Benemid).

Some medications may interact with Glucophage. Tell your doctor if you are using any of the following drugs:

• furosemide (Lasix);
• nifedipine (Adalat, Procardia);
• cimetidine (Tagamet) or ranitidine (Zantac);
• amiloride (Midamor) or triamterene (Dyrenium);
• digoxin (Lanoxin);
• morphine (MS Contin, Kadian, Oramorph);
• procainamide (Procan, Pronestyl, Procanbid);
• quinidine (Cardioquin, Quinidex, Quinaglute);
• trimethoprim (Proloprim, Primsol, Bactrim, Cotrim, Septra); or
• vancomycin (Vancocin, Lyphocin).

This list is not complete and there may be other drugs that can interact with Glucophage . Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor

What should I avoid while taking Glucophage (Metformin)?
Avoid excessive alcohol intake while taking metformin. Together, alcohol and metformin may increase the risk of lactic acidosis and hypoglycemia.
Follow diet, medication, and exercise routines closely. Changing any of these things can affect blood sugar levels.
Tell your doctor or other health care provider that you are taking this medication if you need to have surgery or x-ray procedures that require injection of contrast agents. Treatment with metformin may need to be stopped for a short period of time.
Do not take any over-the-counter cough, cold, allergy, pain, or weight-loss medications without first talking to your doctor.
Some conditions may increase the risk of developing lactic acidosis while taking metformin. Tell your doctor that you are taking metformin if you become ill; if you have a heart attack; have a stroke; develop congestive heart failure; experience diarrhea, vomiting, fever, or dehydration from any cause; decrease the amount of food or liquid in your normal diet, or develop other health conditions. You may need to stop treatment with metformin for a short amount of time until you are feeling better.

Contraindications
Metformin is contraindicated in patients with:
1. 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.
2. Known hypersensitivity to Metformin hydrochloride.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Metformin 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.

Warnings
Lactic Acidosis:
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to Metformin accumulation during treatment with Metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When Metformin is implicated as the cause of lactic acidosis, Metformin plasma levels >5 ?g/mL are generally found.
The reported incidence of lactic acidosis in patients receiving Metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to Metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient�s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Metformin and by use of the minimum effective dose of Metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ? 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Metformin, since alcohol potentiates the effects of Metformin hydrochloride on lactate metabolism. In addition, Metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient�s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood Metformin levels may be useful. Once a patient is stabilized on any dose level of Metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because Metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated Metformin. Such management often results in prompt reversal of symptoms and recovery.

Precautions
Monitoring of renal function
Metformin is known to be substantially excreted by the kidney, and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin. In patients with advanced age, Metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those > 80 years of age, renal function should be monitored regularly and, generally, Metformin should not be titrated to the maximum dose.
Before initiation of Metformin therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or Metformin dispostion
Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of Metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving Metformin. Therefore, in patients in whom any such study is planned, Metformin should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states
Cardiovascular collapse (shock) from whatever cause, 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. When such events occur in patients on Metformin therapy, the drug should be promptly discontinued.

Surgical procedures
Metformin therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient�s oral intake has resumed and renal function has been evaluated as normal.

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.

Impaired hepatic function
Since impaired hepatic function has been associated with some cases of lactic acidosis, Metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels
In controlled clinical trials of Metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin and any apparent abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well controlled on Metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and Metformin levels.If acidosis of either form occurs, Metformin must be stopped immediately and other appropriate corrective measures initiated.

Hypoglycemia
Hypoglycemia does not occur in patients receiving Metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation,or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Loss of control of blood glucose
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin and temporarily administer insulin. Metformin may be reinstituted after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin or sulfonylurea monotherapy, combined therapy with Metformin and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

Information For Patients

Carcinogenesis/ Mutagenesis/ Impairment of Fertility
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with Metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with Metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of mutagenic potential of Metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by Metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy
Teratogenic Effects: Pregnancy Category B
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Metformin should not be used during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant women with Metformin. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to Metformin.

Nursing Mothers
Studies in lactating rats show that Metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, 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.
If Metformin is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use
The safety and effectiveness of Metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years).
Use of Metformin in this age group is supported by evidence from adequate and well-controlled studies of Metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults.
A maximum daily dose of 2000 mg is recommended.

Geriatric Use
Controlled clinical studies of Metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Metformin.

Product description

Most Important Information about Glucophage (Metformin)

Pharmacokinetics

More information about Glucophage (Metformin):

Cancer Benefit for Diabetes Drug Glucophage

Kidney Fund concerned about Glucophage fatality risk

FDA approves new indication for Glucovance oral antidiabetic

For more information look HERE: My Family Drugstore