Metformin hydrochloride

INDICATIONS AND USAGE Metformin hydrochloride extended release tablets USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults 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 hydrochloride extended release tablets USP or any other pharmacologic agent. Dosage of metformin hydrochloride extended release tablets 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 hydrochloride extended release tablets USP in adults is 2000 mg. Metformin hydrochloride extended release tablets USP should generally be given once daily with the evening meal. Metformin hydrochloride extended release tablets 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 hydrochloride extended release tablets 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 hydrochloride extended release tablets 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 hydrochloride extended release tablets USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Metformin hydrochloride extended release tablets USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended release tablets USP will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)

WARNINGS

CONTRAINDICATIONS Metformin hydrochloride are contraindicated in patients with: 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 WARNINGS and PRECAUTIONS ). Known hypersensitivity to metformin hydrochloride. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. Metformin hydrochloride 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. )

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin Hydrochloride Tablets) Glyburide - In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant Metformin Hydrochloride Extended Release Tablets USP and Oral Sulfonylurea Therapy in Adult Patients ). Furosemide - A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically. Nifedipine - A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. Cationic drugs - Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride extended release tablets USP and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. Other - Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin hydrochloride extended release tablets USP, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended release tablets USP, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the s…

Pregnancy Teratogenic Effects: Pregnancy Category B Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, metformin hydrochloride should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with metformin hydrochloride extended release tablets USP. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers 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 hydrochloride extended release tablets USP is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

ADVERSE REACTIONS In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended release tablets USP in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended release tablets USP and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended release tablets USP patients, and that were more common in metformin hydrochloride extended release tablets USP - than placebo-treated patients, are listed in Table 12. Table 12: Most Common Adverse Reactions (>5.0 Percent) in Placebo-Controlled Studies of Metformin Hydrochloride Extended Release Tablets USP* Metformin Hydrochloride Extended Release Tablets USP ( n = 781 ) Placebo ( n = 195 ) Adverse Reaction % of Patients Diarrhea 9.6 2.6 Nausea/Vomiting 6.5 1.5 * Reactions that were more common in metformin hydrochloride extended release tablets USP - than placebo-treated patients. Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended release tablets USP. Additionally, the following adverse reactions were reported in ≥1.0% - ≤5.0% of metformin hydrochloride extended release tablets USP patients and were more commonly reported with metformin hydrochloride extended release tablets USP than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.