Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1837
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Metformin Hydrochloride (Tablet, Film Coated)
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There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin or any other pharmacologic agent. Dosage of metformin 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 metformin hydrochloride tablets is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age); the maximum recommended daily dose of metformin hydrochloride extended-release tablets in adults is 2000 mg. Metformin hydrochloride tablets should be given in divided doses with meals while metformin hydrochloride extended-release tablets should generally be given once daily with the evening meal. Metformin 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 Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. 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, either when used as monotherapy or in combination with sulfonylurea or insulin. 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 metformin may be sufficient during periods of transient loss of control in patients usually well controlled on diet alone. Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)<br/>Recommended Dosing Schedule:<br/>Adults: 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 tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, metformin hydrochloride tablets may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals. The usual starting dose of metformin hydrochloride extended-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. If glycemic control is not achieved on metformin hydrochloride extended-release tablets 2000 mg once daily, a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily should be considered. If higher doses of metformin are required, metformin hydrochloride tablets should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. In a randomized trial, patients currently treated with metformin hydrochloride tablets were switched to metformin hydrochloride extended-release tablets. Results of this trial suggest that patients receiving metformin hydrochloride tablet treatment may be safely switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin hydrochloride tablets to metformin hydrochloride extended-release tablets, glycemic control should be closely monitored and dosage adjustments made accordingly .<br/>Pediatrics: The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.<br/>Transfer from Other Antidiabetic Therapy: When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.<br/>Concomitant Metformin and Oral Sulfonylurea Therapy in Adult Patients: If patients have not responded to 4 weeks of the maximum dose of metformin monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin 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 metformin 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 metformin HCl 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin HCl and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbAand plasma glucose response . However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin 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 one to three months of concomitant therapy with the maximum dose of metformin and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin.<br/>Concomitant Metformin and Insulin Therapy in Adult Patients: The current insulin dose should be continued upon initiation of metformin therapy. Metformin therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin should be increased by 500 mg after approximately one week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for metformin hydrochloride tablets and 2000 mg for metformin hydrochloride extended-release tablets. 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. Further adjustment should be individualized based on glucose-lowering response.<br/>Specific Patient Populations: Metformin is not recommended for use in pregnancy. Metformin hydrochloride tablets are not recommended in patients below the age of 10 years. Metformin hydrochloride extended-release tablets are not recommended in pediatric patients (below the age of 17 years). The initial and maintenance dosing of metformin 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. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.
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Metformin is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-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 pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Metformin hydrochloride tablets, USP contain 500 mg, 850 mg or 1000 mg of metformin hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, titanium dioxide and triacetin. Metformin hydrochloride extended-release tablets contain 500 mg or 750 mg of metformin hydrochloride, USP as the active ingredient. In addition, each tablet contains the following inactive ingredients: carnauba wax, colloidal silicon dioxide, magnesium stearate, polyethylene glycol and stearic acid. In addition, the 500 mg extended-release tablets contain dibasic calcium phosphate (anhydrous).
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Mechanism of Action: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.<br/>Pharmacokinetics:<br/>Absorption and Bioavailability: The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin hydrochloride 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Following a single oral dose of metformin hydrochloride extended-release, Cis achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride, however, the extent of absorption (as measured by AUC) is similar to metformin hydrochloride. At steady-state, the AUC and Care less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma. Within-subject variability in Cand AUC of metformin from metformin hydrochloride extended-release tablets is comparable to that with metformin hydrochloride tablets. Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cand Tof metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.<br/>Distribution: The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets, 850 mg averaged 654��358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally<1 mcg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.<br/>Metabolism and Elimination: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.<br/>Special Populations:
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Metformin is contraindicated in patients with: 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.
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Metformin Hydrochloride Tablets, USP are available containing 500 mg, 850 mg and 1000 mg of metformin hydrochloride, USP. The 500 mg tablets are white film-coated, round, unscored tablets debossed with M on one side of the tablet and 234 on the other side. They are available as follows: NDC 0378-0234-01bottles of 100 tablets NDC 0378-0234-05bottles of 500 tablets NDC 0378-0234-10bottles of 1000 tablets The 850 mg tablets are white film-coated, round, unscored tablets debossed with M on one side of the tablet and 240 on the other side. They are available as follows: NDC 0378-0240-01bottles of 100 tablets NDC 0378-0240-05bottles of 500 tablets The 1000 mg tablets are white film-coated, oval, scored tablets debossed with M 244 on one side of the tablet and scored on the other side. They are available as follows: NDC 0378-0244-01bottles of 100 tablets NDC 0378-0244-05bottles of 500 tablets Metformin Hydrochloride Extended-release Tablets are available containing 500 mg and 750 mg of metformin hydrochloride, USP. The 500 mg extended-release tablets are tan, oval, unscored tablets debossed with M 352 on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-0352-01bottles of 100 tablets NDC 0378-0352-05bottles of 500 tablets The 750 mg extended-release tablets are tan, oval, unscored tablets debossed with M 350 on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-0350-01bottles of 100 tablets NDC 0378-0350-05bottles of 500 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient.
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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 mcg/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 riskof 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 patientand 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, areunlikely 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 hydrochloride tablets or metformin hydrochloride extended-release tablets, 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.
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dailymed-ingredient:crospovidone,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polydextrose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:povidone,
dailymed-ingredient:sodium_lauryl_sulfate,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triacetin
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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 . 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 metforminoverdosage is suspected.
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Metformin Hydrochloride
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Metformin Hydrochloride (Tablet, Film Coated)
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In a U.S. double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablet therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablet patients, and that were more common in metformin hydrochloride tablet- than placebo-treated patients, are listed in Table 11. Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in���1 to���5% of metformin hydrochloride tablet patients and were more commonly reported with metformin hydrochloride tablets 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 metformin hydrochloride extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablet patients, and that were more common in metformin hydrochloride extended-release tablet- than placebo-treated patients, are listed in Table 12. Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in���1% to���5% of metformin hydrochloride extended-release tablet patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.<br/>Pediatric Patients: In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.
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Metformin, as monotherapy, is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. Metformin hydrochloride tablets are indicated in patients 10 years of age and older and metformin hydrochloride extended-release tablets are indicated in patients 17 years of age and older. Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age and older).
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Metformin Hydrochloride
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