No

Antidiabetic Agent (Biguanide)

Management of noninsulin-dependent diabetes mellitus (type 2) as monotherapy when hyperglycemia cannot be managed on diet alone. May be used concomitantly with a sulfonylurea when diet and metformin or sulfonylurea alone do not result in adequate glycemic control.

B

Hypersensitivity to metformin or any component; renal disease or renal dysfunction (serum creatinine greater than or equal to 1.5 mg/dL in males or greater than or equal to 1.4 mg/dL in females or creatinine clearance <60 mL/minute) which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia; acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis); should be temporarily withheld (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) in patients undergoing radiologic studies involving the parenteral administration of iodinated contrast materials (potential for acute alteration in renal function)

Administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Metformin is substantially excreted by the kidney - the risk of accumulation and lactic acidosis increases with the degree of impairment of renal function. Patients with renal function below the limit of normal for their age should not receive metformin. In elderly patients, renal function should be monitored regularly. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may affect metformin disposition. Therapy should be suspended for any surgical procedures. Avoid use in patients with impaired liver function. Metformin should be discontinued at the time of or prior to the procedure in patients undergoing radiologic studies in which intravascular iodinated contrast materials are utilized, and withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been re-evaluated and found to be normal.

>10%: Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, epigastric fullness, constipation, heartburn

1% to 10%:

Dermatologic: Rash, urticaria, photosensitivity

Miscellaneous: Decreased vitamin B₁₂ levels

<1%: Blood dyscrasias, aplastic anemia, hemolytic anemia, bone marrow suppression, thrombocytopenia, agranulocytosis

Hypoglycemia has not been observed with ingestions of up to 85 g of metformin, although lactic acidosis has occurred in such circumstances

Metformin is dialyzable with a clearance of up to 170 mL/minute; hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected

Decreased effect: Drugs which tend to produce hyperglycemia (eg, diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid) may lead to a loss of glycemic control

Increased effect: Furosemide increased the metformin plasma and blood C_max without altering metformin renal clearance in a single dose study

Increased toxicity:

Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) which are eliminated by renal tubular secretion could have the potential for interaction with metformin by competing for common renal tubular transport systems

Cimetidine increases (by 60%) peak metformin plasma and whole blood concentrations

Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)

Onset of effect: Within days, maximum effects up to 2 weeks

Distribution: V_d: 654±358 L

Protein binding: 92% to 99%

Protein binding, plasma: negligible

Bioavailability, absolute: 50% to 60% under fasting conditions; food decreases the extent and slightly delays the absorption; the clinical relevance is unknown

Half-life, plasma elimination: 6.2 hours

Elimination: Renal; tubular secretion is major route

Oral (allow 1-2 weeks between dose titrations): Generally, clinically significant responses are not seen at doses <1500 mg daily; however, a lower recommended starting dose and gradual increased dosage is recommended to minimize gastrointestinal symptoms

500 mg tablets: Initial: 500 mg twice daily (give with the morning and evening meals). Dosage increases should be made in increments of 1 tablet every week, given in divided doses, up to a maximum of 2500 mg/day. Doses of up to 2000 mg/day may be given twice daily. If a dose of 2500 mg/day is required, it may be better tolerated 3 times/day (with meals).

850 mg tablets: Initial: 850 mg once daily (give with the morning meal). Dosage increases should be made in increments of 1 tablet every other week, given in divided doses, up to a maximum of 2550 mg/day. Usual maintenance dose: 850 mg twice daily (with the morning and evening meals). Some patients may be given 850 mg 3 times/day (with meals).

Elderly: The initial and maintenance dosing should be conservative, due to the potential for decreased renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin.

Transfer from other antidiabetic agents: No transition period is generally necessary except when transferring from chlorpropamide. When transferring 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.

Concomitant metformin and oral sulfonylurea therapy: If patients have not responded to 4 weeks of the maximum dose of metformin monotherapy, consideration to a 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.

Dosing adjustment/comments in renal impairment: The plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. Metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine >1.5 mg/dL in males or >1.4 mg/dL in females or an abnormal creatinine clearance.

Dosing adjustment in hepatic impairment: No studies have been conducted, however, metformin should be avoided because the presence of liver disease is a risk factor for the development of lactic acidosis during metformin therapy.

Alcohol: Incidence of lactic acidosis may be increased; avoid or limit use

Food: Food decreases the extent and slightly delays the absorption. Drug may cause GI upset; take with food to decrease GI upset.

Glucose: Decreases blood glucose concentration. Hypoglycemia does not usually occur unless a patient is predisposed. Monitor blood glucose concentration. Exercise caution with administration in patients predisposed to hypoglycemia (eg, cases of reduced caloric intake, strenuous exercise without repletion of calories, alcohol ingestion or when metformin is combined with another oral antidiabetic agent).

Vitamin B₁₂: Decreases absorption of Vitamin B₁₂; monitor for signs and symptoms of vitamin B₁₂ deficiency

Folic acid: Decreases absorption of folic acid; monitor for signs and symptoms of folic acid deficiency

Urine for glucose and ketones, fasting blood glucose, hemoglobin A_1c, and fructosamine. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function should be performed, at least annually. While megaloblastic anemia has been rarely seen with metformin, if suspected, vitamin B₁₂ deficiency should be excluded.

Target range: Adults:

Glycosylated hemoglobin: <7%

None reported

May cause leukopenia; use caution with clozapine and carbamazepine; concurrent use with psychotropics may produce additive sedation

No information available to require special precautions

Metformin-dependent diabetics (noninsulin dependent, type 2) should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia

This medication is used to control diabetes; it is not a cure. Other components of treatment plan are important: follow prescribed diet, medication, and exercise regimen. Take exactly as directed; with meal(s) at the same time each day. Do not change dose or discontinue without consulting prescriber. Avoid alcohol while taking this medication; could cause severe reaction. Inform prescriber of all other prescription or OTC medications you are taking; do not introduce new medication without consulting prescriber. Do not take other medication within 2 hours of this medication unless so advised by prescriber. Maintain regular dietary intake and exercise routine and always carry quick source of sugar with you. You may experience side effects during first weeks of therapy (headache, nausea); consult prescriber if these persist. Report severe or persistent side effects, extended vomiting or flu-like symptoms, skin rash, easy bruising or bleeding, or change in color of urine or stool. Breast-feeding precautions: Breast-feeding is not recommended.

Patients who are NPO may need to have their dose held to avoid hypoglycemia

Tablet, as hydrochloride: 500 mg, 625 mg, 750 mg, 850 mg, 1000 mg

Bailey CJ and Turner RC, "Metformin," N Engl J Med, 1996, 334(9):574-9.

Dunn CJ and Peters DH, "Metformin: A Review of Its Pharmacologic Properties and Therapeutic Use in Diabetes Mellitus," Drugs, 1995, 49(5):721-49.

Josephkutty S and Potter JM, "Comparison of Tolbutamide and Metformin in Elderly Diabetic Patients," Diabet Med, 1990, 7(16):510-4.

Lalau JD, Vermersch A, Hary L, et al, "Type 2 Diabetes in the Elderly: An Assessment of Metformin," Int J Clin Pharmacol Ther Toxicol, 1990, 28(8):329-32.

"Standards of Medical Care for Patients With Diabetes Mellitus. American Diabetes Association," Diabetes Care, 1994, 17(6):616-23.