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TABLETS40-8871 · Actavis Elizabeth LLC
Dosage Form
TABLETS40-8871
Manufacturer
Actavis Elizabeth LLC
This medication contains important usage instructions, warnings, and side effect information that you should review before use.
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). 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 hydrochloride tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. ln addition, metformin 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 hydrochloride tablets 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. (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, 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. (See also CONTRAINDICATIONS and PRECAUTIONS).
Metformin hydrochloride tablets, as monotherapy, are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. Metformin is indicated in patients 10 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 nd older).
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 dose. The maximum recommended daily dose of metformin hydrochloride tablets is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age).
Metformin should be given in divided doses with meals and 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 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 hydrochloride tablets, 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.
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 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 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.
Pediatrics: The usual starting dose of metformin 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.
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 two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin Hydrochloride And Oral Sulfonylurea Therapy In Adult Patients: If patients have not responded to four weeks of the maximum dose of metformin hydrochloride monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride tablets 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 hydrochloride and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With metformin hydrochloride 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.
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 tablets 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. 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.
Specific Patient Populations: Metformin is not recommended in patients below the age of 10 years.
Pediatric dosing information for metformin, as monotherapy, is approved for Bristol-Myers Squibb Company's metformin hydrochloride tablets. However, due to Bristol-Myers Squibb's marketing exclusivity rights, this drug product is not labeled for pediatric use.
The initial and maintenance dosing of metformin hydrochloride tablets 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 hydrochloride tablets.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)
Metformin hydrochloride tablets are 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 (see WARNlNGSand PRECAUTIONS).
2. Congestive heart failure requiring pharmacologic treatment.
3. Known hypersensitivity to metformin hydrochloride.
4. 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 (See also PRECAUTIONS).
In a U.S. double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin- than placebo-treated patients, are listed in Table 7.
| Metformin Monotherapy n=141 | Placebo n=145 | |
| Adverse Reactions | % of Patients | |
| * Reactions that were more common in metformin- than placebo-treated patients. | ||
| Diarrhea | 53.2 | 11.7 |
| Nausea/Vomiting | 25.5 | 8.3 |
| Flatulence | 12.1 | 5.5 |
| Asthenia | 9.2 | 5.5 |
| Indigestion | 7.1 | 4.1 |
| Abdominal Discomfort | 6.4 | 4.8 |
| Headache | 5.7 | 4.8 |
Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Additionally, the following adverse reactions were reported in ≥ 1.0-≤ 5.0 % of metformin patients and were more commonly reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
Pediatric Patients:
In clinical trials with metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.
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.
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 10-16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.)
Controlled clinical studies of metformin hydrochloride tablets 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, it should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS and CLINICAL PHARMACOLOGY, Pharmacokinetics). 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 (see also WARNlNGS and DOSAGE AND ADMINISTRATION).
Hypoglycemia has not been seen even with ingestion of up to 85 grams of metformin, although lactic acidosis has occurred in such circumstances (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.
Metformin hydrochloride 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:
[image: MM1]Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•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 contain 500 mg, 850 mg and 1000 mg of metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: crospovidone, hydroxypropyl methylcellulose, maltodextrin, polyethylene glycol, povidone, stearic acid.
Metformin Hydrochloride Tablets are available as follows:
500 mg — Each white to off-white, oval, film coated tablet imprinted with [image: MM2] 657 on one side and plain on the other contains 500 mg of metformin hydrochloride. Tablets are supplied in bottles of 100 (NDC 0228-2657-11) with a child-resistant closure and bottles of 100 (NDC 0228-2657-10), 500 (NDC 0228-2657-50) and 1000 (NDC 0228-2657-96) without a child-resistant closure.
850 mg — Each white to off-white, oval, film coated tablet imprinted with [image: MM3] 715 on one side and plain on the other contains 850 mg of metformin hydrochloride. Tablets are supplied in bottles of 100 (NDC 0228-2715-11) with a child-resistant closure and bottles of 100 (NDC 0228-2715-10), 500 (NDC 0228-2715-50) and 1000 (NDC 0228-2715-96) without a child-resistant closure.
1000 mg — Each white to off-white, oval, film coated tablet imprinted twice with [image: MM4]on one side and twice with 718 on the other and bisected on both sides contains 1000 mg of metformin hydrochloride. Tablets are supplied in bottles of 100 (NDC 0228-2718-11) with a child-resistant closure and bottles of 100 (NDC 0228-2718-10), 500 (NDC 0228-2718-50) and 1000 (NDC 0228-2718-96) without a child-resistant closure.
Dispense in a tight, light-resistant container as defined in the USP.
Store between 15°-30°C (59°-86°F).
Photos of the product and/or packaging supplied by the manufacturer.
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 (except in special circumstances, see PRECAUTIONS) 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.
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 three times the maximum recommended human daily dose on a body surface area basis. 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. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day.
No evidence of a mutagenic potential of metformin was found 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 micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin adminstration 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.
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