Glucophage Information
Glucophage () Description
Glucophage () (metformin hydrochloride) Tablets and Glucophage () XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of CHN • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Glucophage () tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.
Glucophage () XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient.
Glucophage () XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.
Glucophage () XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.
Glucophage () Indications And Usage
Glucophage () (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
Glucophage () XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Glucophage () Contraindications
Glucophage () and Glucophage () XR are contraindicated in patients with:
Glucophage () and Glucophage () XR 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. (See also .)
Glucophage () Precautions
Patients should be informed of the potential risks and benefits of Glucophage () or Glucophage () XR and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the and sections, should be explained to patients. Patients should be advised to discontinue Glucophage () or Glucophage () XR immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Glucophage () or Glucophage () XR, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Glucophage () or Glucophage () XR.
Glucophage () or Glucophage () XR alone does not usually cause hypoglycemia, although it may occur when Glucophage () or Glucophage () XR is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See printed below.)
Patients should be informed that Glucophage () XR must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also ).
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Glucophage () therapy, if this is suspected, vitamin B deficiency should be excluded.
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 4 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 a mutagenic potential of metformin in the following tests: Ames test (), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the 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 3 times the maximum recommended human daily dose based on body surface area comparisons.
The safety and effectiveness of Glucophage () 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 Glucophage () in this age group is supported by evidence from adequate and well-controlled studies of Glucophage () 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. (See .) In this study, adverse effects were similar to those described in adults. (See .) A maximum daily dose of 2000 mg is recommended. (See .)
Safety and effectiveness of Glucophage () XR in pediatric patients have not been established.
Glucophage () Adverse Reactions
In a US double-blind clinical study of Glucophage () in patients with type 2 diabetes, a total of 141 patients received Glucophage () therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the Glucophage () patients, and that were more common in Glucophage () - than placebo-treated patients, are listed in .
Diarrhea led to discontinuation of study medication in 6% of patients treated with Glucophage () . Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of Glucophage () patients and were more commonly reported with Glucophage () than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with Glucophage () XR in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered Glucophage () XR and 195 patients received placebo. Adverse reactions reported in greater than 5% of the Glucophage () XR patients, and that were more common in Glucophage () XR- than placebo-treated patients, are listed in .
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Glucophage () XR. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of Glucophage () XR patients and were more commonly reported with Glucophage () XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Glucophage () Overdosage
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see ). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Glucophage () Dosage And Administration
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Glucophage () or Glucophage () XR or any other pharmacologic agent. Dosage of Glucophage () or Glucophage () XR must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Glucophage () is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of Glucophage () XR in adults is 2000 mg.
Glucophage () should be given in divided doses with meals while Glucophage () XR should generally be given once daily with the evening meal. Glucophage () or Glucophage () XR should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
During treatment initiation and dose titration (see ), fasting plasma glucose should be used to determine the therapeutic response to Glucophage () or Glucophage () XR and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months.
Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.
Short-term administration of Glucophage () or Glucophage () XR may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
If patients have not responded to 4 weeks of the maximum dose of Glucophage () or Glucophage () XR monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Glucophage () or Glucophage () XR at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
With concomitant Glucophage () or Glucophage () XR and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Glucophage () 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of Glucophage () and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA, and plasma glucose response (see ). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Glucophage () or Glucophage () XR and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)
If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of Glucophage () or Glucophage () XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Glucophage () or Glucophage () XR.
Glucophage () or Glucophage () XR are not recommended for use in pregnancy. Glucophage () is not recommended in patients below the age of 10 years. Glucophage () XR is not recommended in pediatric patients (below the age of 17 years).
The initial and maintenance dosing of Glucophage () or Glucophage () XR 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 Glucophage () or Glucophage () XR.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See .)
Glucophage () How Supplied
Glucophage () (metformin hydrochloride) Tablets
Glucophage () 500 mg tablets are round, white to off-white, film-coated tablets debossed with "BMS 6060" around the periphery of the tablet on one side and "500" debossed across the face of the other side.
Glucophage () 850 mg tablets are round, white to off-white, film-coated tablets debossed with "BMS 6070" around the periphery of the tablet on one side and "850" debossed across the face of the other side.
Glucophage () 1000 mg tablets are white, oval, biconvex, film-coated tablets with "BMS 6071" debossed on one side and "1000" debossed on the opposite side and with a bisect line on both sides.
Glucophage () XR (metformin hydrochloride) Extended-Release Tablets
Glucophage () XR 500 mg tablets are white to off-white, capsule shaped, biconvex tablets, with "BMS 6063" debossed on one side and "500" debossed across the face of the other side.
Glucophage () XR 750 mg tablets are capsule shaped, biconvex tablets, with "BMS 6064" debossed on one side and "750" debossed on the other side. The tablets are pale red and may have a mottled appearance.
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