Metformin hydrochloride 500 MG Oral Tablet
Generic Name: METFORMIN HYDROCHLORIDE
Brand Name: Metformin Hydrochloride
- Substance Name(s):
- METFORMIN HYDROCHLORIDE
WARNINGS
Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Metformin HCl; 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 HCl 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 HCl and by use of the minimum effective dose of Metformin HCl.
In particular, treatment of the elderly should be accompanied by careful monitoring of renal function.
Metformin HCl 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 HCl 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 HCl 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 HCl, since alcohol potentiates the effects of metformin HCl on lactate metabolism.
In addition, Metformin HCl should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS ).
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 (see also PRECAUTIONS ).
Metformin HCl 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 HCl, 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 HCl 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.
(See also PRECAUTIONS .) 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 HCl, the drug should be discontinued immediately and general supportive measures promptly instituted.
Because metformin HCl 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.
(See also CONTRAINDICATIONS and PRECAUTIONS .)
OVERDOSAGE
Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams.
Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established.
Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ).
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.
DESCRIPTION
Metformin Hydrochloride (HCl) Tablets, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes.
Metformin HCl, USP ( 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 HCl, USP is a white to off-white crystalline compound with a molecular formula of C 4H 11N 5 • HCl and a molecular weight of 165.62.
Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform.
The pK a of metformin is 12.4.
The pH of a 1% aqueous solution of metformin HCl, USP is 6.68.
Metformin HCl Tablets, USP, contains 500 mg, 850 mg, or 1000 mg of metformin HCl, USP.
Each tablet contains the inactive ingredients povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contain polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, gum acacia, maltodextrin, propylene glycol and natural flavors.
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HOW SUPPLIED
Metformin HCl Tablets, USP 500 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed “IP 218” on obverse and “500” on the reverse.
They are available as follows: Bottles of 14, 20, 30, 60, 90, 120 and 180 and 270.
Storage Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature.] Dispense in light-resistant containers.
INDICATIONS AND USAGE
Metformin HCl Tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent.
Dosage of Metformin HCl, USP 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 HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age).
Metformin HCl, USP should be given in divided doses with meals.
Metformin HCl, USP 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 HCl, USP and identify the minimum effective dose for the patient.
Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three 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 HCl, USP, 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 HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Recommended Dosing Schedule 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 HCl Tablets, USP 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 HCl, USP 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.
If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.
(See CLINICAL PHARMACOLOGY, Clinical Studies.) Pediatrics – The usual starting dose of Metformin HCl, USP 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.
Transfer From Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary.
When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP 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 HCl, USP 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, USP 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, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA 1c and plasma glucose response (see CLINICAL PHARMACOLOGY: Clinical Studies).
However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal.
With concomitant Metformin HCl, USP 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 HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP.
Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy.
Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy.
For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved.
The maximum recommended daily dose is 2500 mg for Metformin HCl, USP.
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 HCl, USP.
Further adjustment should be individualized based on glucose-lowering response.
Specific Patient Populations Metformin HCl, USP is not recommended for use in pregnancy.
Metformin HCl, USP is not recommended in patients below the age of 10 years.
The initial and maintenance dosing of Metformin HCl, USP 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 HCl, USP.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.
(See WARNINGS .)