Metformin Hydrochloride (metformin hydrochloride 500 mg) Dailymed

Rx Only

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 C₄H₁₁N₅ • 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, 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.

Clinical Pharmacology

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.

Pharmacokinetics

Absorption and Bioavailability

The absolute bioavailability of a Metformin HCL 500 mg tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of Metformin HCL 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_max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T_max) 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.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin HCL 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 HCL, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL. During controlled clinical trials of Metformin HCL, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

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.

Special Populations

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

Renal Insufficiency

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS).

Hepatic Insufficiency

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Geriatrics

Limited data from controlled pharmacokinetic studies of Metformin HCL in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin HCL Tablets treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).

Table 1: Select Mean ( ± SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCL

Subject Groups: Metformin HCL dose a (number of subjects)	C max b (μg/mL)	T max c (hrs)	Renal Clearance (mL/min)
a All doses given fasting except the first 18 doses of the multiple dose studies
b Peak plasma concentration
c Time to peak plasma concentration
d Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
e Kinetic study done following dose 19, given fasting
f Elderly subjects, mean age 71 years (range 65-81 years)
g CLcr = creatinine clearance normalized to body surface area of 1.73 m2
Healthy, nondiabetic adults:
500 mg single dose (24)	1.03 (±0.33)	2.75 (±0.81)	600 (±132)
850 mg single dose (74) d	1.60 (±0.38)	2.64 (±0.82)	552 (±139)
850 mg three times daily for 19 doses e (9)	2.01 (±0.42)	1.79 (±0.94)	642 (±173)
Adults with type 2 diabetes:
850 mg single dose (23)	1.48 (±0.5)	3.32 (±1.08)	491 (±138)
850 mg three times daily for 19 doses e (9)	1.90 (±0.62)	2.01 (±1.22)	550 (±160)
Elderly f , healthy nondiabetic adults:
850 mg single dose (12)	2.45 (±0.70)	2.71 (±1.05)	412 (±98)
Renal-impaired adults:
850 mg single dose
Mild (CLcr g 61-90 mL/min) (5)	1.86 (±0.52)	3.20 (±0.45)	384 (±122)
Moderate (CLcr 31-60 mL/min) (4)	1.86 (±0.52)	3.75 (±0.50)	108 (±57)
Severe (CLcr 10-30 mL/min) (6)	3.93 (±0.92)	4.01 (±1.10)	130 (±90)

Pediatrics

After administration of a single oral Metformin HCL 500 mg tablet with food, geometric mean metformin C_max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of Metformin HCL was comparable in males and females.

Race

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of Metformin HCL in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies

Metformin Hydrochloride

In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with Metformin HCl (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A_1c (HbA_1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).

Table 2: Metformin HCL vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA_1c, and Body Weight, at Final Visit (29-week study)

	Metformin HCL (n=141)	Placebo (n=145)	p-Value
* All patients on diet therapy at Baseline
**Not statistically significant
FPG (mg/dL)
Baseline	241.5	237.7	NS**
Change at FINAL VISIT	-53.0	6.3	0.001
Hemoglobin A 1c (%)
Baseline	8.4	8.2	NS**
Change at FINAL VISIT	-1.4	0.4	0.001
Body Weight (lbs)
Baseline	201.0	206.0	NS**
Change at FINAL VISIT	-1.4	-2.4	NS**

A 29-week, double-blind, placebo-controlled study of Metformin HCL and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with Metformin HCL 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of Metformin HCL increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed Metformin HCL 2500 mg. Patients in the Metformin HCL only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking Metformin HCL 2000 mg/glyburide 20 mg or Metformin HCL 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to Metformin HCL (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA_1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of Metformin HCL and glyburide was effective in reducing FPG, PPG, and HbA_1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, – 68 mg/dL, and –1.9%, respectively (see Table 3).

Table 3: Combined Metformin HCL/Glyburide (Comb) vs Glyburide (Glyb) or Metformin HCL (Met) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA_1c, and Body Weight, at Final Visit (29-week study)

	Comb (n=213)	Glyb (n=209)	Met (n=210)	p-Values
				Glyb vs Comb	Met vs Comb	Met vs Glyb
*All patients on glyburide, 20 mg/day at Baseline
** Not statistically significant
Fasting Plasma Glucose (mg/dL)
Baseline	250.5	247.5	253.9	NS**	NS**	NS**
Change at FINAL VISIT	-63.5	13.7	-0.9	0.001	0.001	0.025
Hemoglobin A 1c (%)
Baseline	8.8	8.5	8.9	NS**	NS**	0.007
Change at FINAL VISIT	-1.7	0.2	-0.4	0.001	0.001	0.001
Body Weight (lbs)
Baseline	202.2	203.0	204.0	NS**	NS**	NS**
Change at FINAL VISIT	0.9	-0.7	-8.4	0.011	0.001	0.001

The magnitude of the decline in fasting blood glucose concentration following the institution of - Metformin HCL Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, Metformin HCL, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4).

Table 4: Summary of Mean Percent Change From Baseline of Major Serum Lipid Variables at Final Visit (29-week studies)

	Metformin HCL vs Placebo		Combined Metformin HCL /Glyburide vs Monotherapy
	Metformin HCL (n=141)	Placebo (n=145)	Metformin HCL (n=210)	Metformin HCL Glyburide (n=213)	Glyburide (n=209)
Total Cholesterol (mg/dL)
Baseline	211.0	212.3	213.1	215.6	219.6
Mean % Change at FINAL VISIT	-5%	1%	-2%	-4%	1%
Total Triglycerides (mg/dL)
Baseline	236.1	203.5	242.5	215.0	266.1
Mean % Change at FINAL VISIT	-16%	1%	-3%	-8%	4%
LDL-Cholesterol (mg/dL)
Baseline	135.4	138.5	134.3	136.0	137.5
Mean % Change at FINAL VISIT	-8%	1%	-4%	-6%	3%
HDL-Cholesterol (mg/dL)
Baseline	39.0	40.5	37.2	39.0	37.0
Mean % Change at FINAL VISIT	2%	-1%	5%	3%	1%

In contrast to sulfonylureas, body weight of individuals on Metformin HCL tended to remain stable or even decrease somewhat (see Tables 2 and 3).

A 24-week, double-blind, placebo-controlled study of Metformin HCL plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive Metformin HCL plus insulin achieved a reduction in HbA_1c of 2.10%, compared to a 1.56% reduction in HbA_1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, Metformin HCL plus insulin versus insulin plus placebo, respectively, p=0.04.

Table 5: Combined Metformin HCL /Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA_1c and Daily Insulin Dose

	Metformin HCL/Insulin (n=26)	Placebo/ Insulin (n=28)	Treatment Difference Mean ±SE
a Statistically significant using analysis of covariance with baseline as covariate (p=0.04)
Not significant using analysis of variance (values shown in table)
b  Statistically significant for insulin (p=0.04)
Hemoglobin A 1c (%)
Baseline	8.95	9.32
Change at FINAL VISIT	-2.10	-1.56	-0.54±0.43a
Insulin Dose (U/day)
Baseline	93.12	94.64
Change at FINAL VISIT	-0.15	15.93	-16.08±7.77b

A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA_1c of 7.46 ± 0.97%, the addition of Metformin HCL maintained similar glycemic control (HbA_1c 7.15 ± 0.61 versus 6.97 ± 0.62 for Metformin HCL plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for Metformin HCL plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of Metformin HCL plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

A 24-week, double-blind, randomized study of Metformin HCL Tablets, USP taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with Metformin HCL 500 mg twice daily for at least 8 weeks prior to study entry. The Metformin HCL dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA_1c was ≤ 8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 6.

Table 6: Summary of Mean Changes from Baseline* in HbA_1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study)

	Metformin HCL 500 mg Twice Daily
*All patients on Metformin HCL 500 mg twice daily at Baseline
a n=68
Hemoglobin A 1c (%)	(n=67)
Baseline	7.06
Change at 12 weeks	0.14
(95% CI)	(-0.03, 0.31)
Change at FINAL VISIT	0.14a
(95% CI)	(-0.04, 0.31)
FPG (mg/dL)	(n=69)
Baseline	127.2
Change at 12 weeks	12.9
(95% CI)	(6.5, 19.4)
Change at FINAL VISIT	14.0
(95% CI)	(7.0, 21.0)
Body Weight (lbs)	(n=71)
Baseline	210.3
Change at 12 weeks	0.4
(95% CI)	(-0.4, 1.5)
Change at FINAL VISIT	0.9
(95% CI)	(-0.4, 2.2)

Changes in lipid parameters in the previously described study of Metformin HCL are shown in Table 7.

Table 7: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study)

	Metformin HCL 500 mg Twice Daily
* All patients on Metformin HCL 500 mg twice daily at Baseline
Total Cholesterol (mg/dL)	(n=68)
Baseline	199.0
Mean % Change at FINAL VISIT	0.1%
Total Triglycerides (mg/dL)	(n=68)
Baseline	178.0
Mean % Change at FINAL VISIT	6.3%
LDL-Cholesterol (mg/dL)	(n=68)
Baseline	122.1
Mean % Change at FINAL VISIT	-1.3%
HDL-Cholesterol (mg/dL)	(n=68)
Baseline	41.9
Mean % Change at FINAL VISIT	4.8%

In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with Metformin HCL (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 8).

Table 8: Metformin HCL vs Placebo (Pediatrics^a) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit

	Metformin HCL	Placebo	p-Value
a Pediatric patients mean age 13.8 years (range 10-16 years)
* All patients on diet therapy at Baseline
**Not statistically significant
FPG (mg/dL)	(n=37)	(n=36)	<0.001
Baseline	162.4	192.3
Change at FINAL VISIT	-42.9	21.4
Body Weight (lbs)	(n=39)	(n=38)	NS**
Baseline	205.3	189.0
Change at FINAL VISIT	-3.3	-2.0

Indications And Use

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.

Contraindications

Metformin HCL, USP is 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 WARNINGS and PRECAUTIONS).

2. Known hypersensitivity to Metformin HCL, USP.

3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Metformin HCL, USP 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.)

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 μg/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 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 hydrochloride 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 .)

Precautions

General

Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Metformin HCL or any other anti-diabetic drug. Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCL. In patients with advanced age, Metformin HCL should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin HCL should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).

Before initiation of Metformin HCL therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin HCL discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)—Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Metformin HCL should be temporarily discontinued 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.

Hypoxic states—Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin HCL therapy, the drug should be promptly discontinued.

Surgical procedures— Metformin HCL therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCL.

Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic acidosis, Metformin HCL should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B ₁₂ levels—In controlled clinical trials of Metformin HCL of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin HCL or Vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin HCL and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).

Certain individuals (those with inadequate Vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B₁₂ levels. In these patients, routine serum Vitamin B₁₂ measurements at two- to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes—A patient with type 2 diabetes previously well controlled on Metformin HCL who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Metformin HCL must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Hypoglycemia—Hypoglycemia does not occur in patients receiving Metformin HCL alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin HCL and temporarily administer insulin. Metformin HCL may be reinstituted after the acute episode is resolved.

The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin HCL or sulfonylurea monotherapy, combined therapy with Metformin HCL and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin HCL /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

Information for Patients

Patients should be informed of the potential risks and benefits of Metformin HCL and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Metformin HCL immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin HCL, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Metformin HCL.

Metformin HCL alone does not usually cause hypoglycemia, although it may occur when Metformin HCL is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)

Laboratory Tests

Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCL therapy, if this is suspected, Vitamin B₁₂ deficiency should be excluded.

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin HCL)

Glyburide—In a single-dose interaction study in type 2 diabetes patients, co-administration 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 HCL 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 co-administration. 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 co-administered chronically.

Nifedipine—A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration 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 HCL 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 HCL, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin HCL, 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 co-administered 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 sulfonylureas, which are extensively bound to serum proteins.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. 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. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin 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 mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered 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.

Pregnancy

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 HCL should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with Metformin HCL. 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 HCL is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and effectiveness of Metformin HCL 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 HCL in this age group is supported by evidence from adequate and well-controlled studies of Metformin HCL 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.)

Geriatric Use

Controlled clinical studies of Metformin HCL 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, Metformin HCL 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 HCL 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 HCL (see also WARNINGS and DOSAGE AND ADMINISTRATION).