Metformin Hydrochloride (metformin hydrochloride 750 mg) Dailymed

Description

Metformin hydrochloride extended-release tablets USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride, 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:

C₄H₁₁N₅•HCl M.W. 165.63

Metformin hydrochloride, USP is a white to off-white crystalline compound. Metformin hydrochloride, 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 hydrochloride, USP is 6.68.

Metformin hydrochloride extended-release tablets USP contain 500 mg or 750 mg of metformin hydrochloride, USP as the active ingredient. In addition, each tablet contains the following inactive ingredients: ethylcellulose, hypromellose, magnesium stearate and microcrystalline cellulose. The 750 mg tablet also contains ferric oxide red and ferric oxide yellow.

Metformin hydrochloride extended-release tablets USP meet USP Dissolution Test 2.

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

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 to 1500 mg, and 850 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.

Following a single oral dose of metformin hydrochloride extended-release tablets, C_max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is similar to metformin hydrochloride tablets.

At steady state, the AUC and C_max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.

Within-subject variability in C_max and AUC of metformin from metformin hydrochloride extended-release tablets is comparable to that with metformin hydrochloride tablets.

Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablet increased by approximately 50% when given with food, there was no effect of food on C_max and T_max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.

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

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.

Specific Populations

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.

The pharmacokinetics of metformin hydrochloride extended-release tablets in patients with type 2 diabetes are comparable to those in healthy normal adults.

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 1; also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS).

Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets 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; also see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Table 1: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

Subject Groups: metformin hydrochloride tablet dose All doses given fasting except the first 18 doses of the multiple dose studies (number of subjects)	Cmax Peak plasma concentration (mcg/mL)	Tmax Time to peak plasma concentration (hrs)	Renal Clearance (mL/min)
Healthy, nondiabetic adults:
500 mg single dose (24)	1.03 (± 0.33)	2.75 (± 0.81)	600 (± 132)
850 mg single dose (74)Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)	1.60 (± 0.38)	2.64 (± 0.82)	552 (± 139)
850 mg three times daily for 19 dosesKinetic study done following dose 19, given fasting (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 (9)	1.90 (± 0.62)	2.01 (± 1.22)	550 (± 160)
Elderly Elderly subjects, mean age 71 years (range 65 to 81 years), 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 CLcr = creatinine clearance normalized to body surface area of 1.73 m2 61 to 90 mL/min) (5)	1.86 (± 0.52)	3.20 (± 0.45)	384 (± 122)
Moderate (CLcr 31 to 60 mL/min) (4)	4.12 (± 1.83)	3.75 (± 0.50)	108 (± 57)
Severe (CLcr 10 to 30 mL/min) (6)	3.93 (± 0.92)	4.01 (± 1.10)	130 (± 90)

After administration of a single oral metformin hydrochloride 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.

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 hydrochloride tablets was comparable in males and females.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride tablets 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 Tablets

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 hydrochloride tablets (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 Hydrochloride Tablets vs Placebo Summary of Mean Changes From BaselineAll patients on diet therapy at Baseline in Fasting Plasma Glucose, HbA_1c, and Body Weight, at Final Visit (29 Week Study)

	Metformin Hydrochloride Tablets (n = 141)	Placebo (n = 145)	p-Value
FPG (mg/dL)
Baseline	241.5	237.7	NSNot statistically significant
Change at FINAL VISIT	–53.0	6.3	0.001
Hemoglobin A1c(%)
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 hydrochloride tablets 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 hydrochloride tablets 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of metformin hydrochloride tablets increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride tablets 2500 mg. Patients in the metformin hydrochloride tablets 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 hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA_1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to metformin hydrochloride tablets (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 hydrochloride tablets 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 Hydrochloride Tablets/Glyburide (Comb) vs Glyburide (Glyb) or Metformin Hydrochloride Tablet Monotherapy: Summary of Mean Changes From BaselineAll patients on glyburide, 20 mg/day, at Baseline in Fasting Plasma Glucose, HbA_1c, and Body Weight, at Final Visit (29 Week Study)

	Comb (n = 213)	Glyb (n = 209)	Metformin Hydrochloride Tablet (n = 210)	p-values
				Glyb vs Comb	Metformin Hydrochloride Tablet vs Comb	Metformin Hydrochloride Tablet vs Glyb
Fasting Plasma Glucose (mg/dL)
Baseline	250.5	247.5	253.9	NSNot statistically significant	NS	NS
Change at FINAL VISIT	–63.5	13.7	–0.9	0.001	0.001	0.025
Hemoglobin A1c(%)
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 hydrochloride tablet 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 hydrochloride tablets, 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 Hydrochloride Tablets vs Placebo		Combined Metformin Hydrochloride Tablets/Glyburide vs Monotherapy
	Metformin Hydrochloride Tablets (n = 141)	Placebo (n = 145)	Metformin Hydrochloride Tablets (n = 210)	Metformin Hydrochloride Tablets/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 hydrochloride tablets tended to remain stable or even decrease somewhat (see Tables 2 and 3).

A 24 week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets plus insulin versus insulin plus placebo, respectively, p = 0.04.

Table 5: Combined Metformin Hydrochloride Tablets/Insulin vs Placebo/Insulin Summary of Mean Changes From Baseline in HbA_1c and Daily Insulin Dose

	Metformin Hydrochloride Tablets/Insulin (n = 26)	Placebo/Insulin (n = 28)	Treatment Difference Mean ± SE
Hemoglobin A1c(%)
Baseline	8.95	9.32
Change at FINAL VISIT	–2.10	–1.56	–0.54 ± 0.43Statistically significant using analysis of covariance with baseline as covariate (p = 0.04) Not significant using analysis of variance (values shown in table)
Insulin Dose (U/day)
Baseline	93.12	94.64
Change at FINAL VISIT	–0.15	15.93	–16.08 ± 7.77Statistically significant for insulin (p = 0.04)

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 hydrochloride tablets maintained similar glycemic control (HbA_1c 7.15 ± 0.61 vs 6.97 ± 0.62 for metformin hydrochloride tablets plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 units for metformin hydrochloride tablets plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin hydrochloride tablets 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.

Metformin Hydrochloride Extended-Release Tablets

A 24 week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA_1c 7.0% to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA_1c of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA_1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA_1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin hydrochloride extended-release tablets 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA_1c was > 7.0% but < 8.0% (patients with HbA_1c > 8.0% were discontinued from the study). At the final visit (24 week), mean HbA_1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended-release tablets.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA_1c 7.0% to 11.0%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.

Table 6: Summary of Mean Changes From BaselineAll patients on diet therapy at Baseline in HbA_1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16 Week Study)

	Metformin Hydrochloride Extended-Release Tablets					Placebo
	500 mg Once Daily	1000 mg Once Daily	1500 mg Once Daily	2000 mg Once Daily	1000 mg Twice Daily
Hemoglobin A1c (%)	(n = 115)	(n = 115)	(n = 111)	(n = 125)	(n = 112)	(n = 111)
Baseline	8.2	8.4	8.3	8.4	8.4	8.4
Change at FINAL VISIT	–0.4	–0.6	–0.9	–0.8	–1.1	0.1
p-valueAll comparisons versus Placebo	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	–
FPG (mg/dL)	(n = 126)	(n = 118)	(n = 120)	(n = 132)	(n = 122)	(n = 113)
Baseline	182.7	183.7	178.9	181.0	181.6	179.6
Change at FINAL VISIT	–15.2	–19.3	–28.5	–29.9	–33.6	7.6
p-value	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	–
Body Weight (lbs)	(n = 125)	(n = 119)	(n = 117)	(n = 131)	(n = 119)	(n = 113)
Baseline	192.9	191.8	188.3	195.4	192.5	194.3
Change at FINAL VISIT	–1.3	–1.3	–0.7	–1.5	–2.2	–1.8
p-value	NSNot statistically significant	NS	NS	NS	NS	–

Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin hydrochloride tablets and metformin hydrochloride extended-release tablets).

A 24 week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablet 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 7.

Table 7: Summary of Mean Changes From BaselineAll patients on metformin hydrochloride tablets 500 mg twice daily at Baseline in HbA_1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24 Week Study)

	Metformin Hydrochloride Tablets	Metformin Hydrochloride Extended-Release Tablets
	500 mg Twice Daily	1000 mg Once Daily	1500 mg Once Daily
Hemoglobin A1c (%)	(n = 67)	(n = 72)	(n = 66)
Baseline	7.06	6.99	7.02
Change at 12 Weeks	0.14	0.23	0.04
(95% CI)	(–0.03, 0.31)	(0.10, 0.36)	(–0.08, 0.15)
Change at FINAL VISIT	0.14n = 68	0.27	0.13
(95% CI)	(–0.04, 0.31)	(0.11, 0.43)	(–0.02, 0.28)
FPG (mg/dL)	(n = 69)	(n = 72)	(n = 70)
Baseline	127.2	131.0	131.4
Change at 12 Weeks	12.9	9.5	3.7
(95% CI)	(6.5, 19.4)	(4.4, 14.6)	(–0.4, 7.8)
Change at FINAL VISIT	14.0	11.5	7.6
(95% CI)	(7.0, 21.0)	(4.4, 18.6)	(1.0, 14.2)
Body Weight (lbs)	(n = 71)	(n = 74)	(n = 71)
Baseline	210.3	202.8	192.7
Change at 12 Weeks	0.4	0.9	0.7
(95% CI)	(–0.4, 1.5)	(0.0, 2.0)	(–0.4, 1.8)
Change at FINAL VISIT	0.9	1.1	0.9
(95% CI)	(–0.4, 2.2)	(–0.2, 2.4)	(–0.4, 2.0)

After 12 weeks of treatment, there was an increase in mean HbA_1c in all groups; in the metformin hydrochloride extended-release tablets 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).

Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended-release tablets are shown in Table 8.

Table 8: Summary of Mean Percent Changes From BaselineAll patients on diet therapy at Baseline in Major Lipid Variables at Final Visit (16 Week Study)

	Metformin Hydrochloride Extended-Release Tablets					Placebo
	500 mg Once Daily	1000 mg Once Daily	1500 mg Once Daily	2000 mg Once Daily	1000 mg Twice Daily
Total Cholesterol (mg/dL)	(n = 120)	(n = 113)	(n = 110)	(n = 126)	(n = 117)	(n = 110)
Baseline	210.3	218.1	214.6	204.4	208.2	208.6
Mean % Change at FINAL VISIT	1.0%	1.7%	0.7%	–1.6%	–2.6%	2.6%
Total Triglycerides (mg/dL)	(n = 120)	(n = 113)	(n = 110)	(n = 126)	(n = 117)	(n = 110)
Baseline	220.2	211.9	198.0	194.2	179.0	211.7
Mean % Change at FINAL VISIT	14.5%	9.4%	15.1%	14.9%	9.4%	10.9%
LDL-Cholesterol (mg/dL)	(n = 119)	(n = 113)	(n = 109)	(n = 126)	(n = 117)	(n = 107)
Baseline	131.0	134.9	135.8	125.8	131.4	131.9
Mean % Change at FINAL VISIT	–1.4%	–1.6%	–3.5%	–3.3%	–5.5%	3.2%
HDL-Cholesterol (mg/dL)	(n = 120)	(n = 108)	(n = 108)	(n = 125)	(n = 117)	(n = 108)
Baseline	40.8	41.6	40.6	40.2	42.4	39.4
Mean % Change at FINAL VISIT	6.2%	8.6%	5.5%	6.1%	7.1%	5.8%

Changes in lipid parameters in the previously described study of metformin hydrochloride tablets and metformin hydrochloride extended-release tablets are shown in Table 9.

Table 9: Summary of Mean Percent Changes From BaselineAll patients on metformin hydrochloride tablets 500 mg twice daily at Baseline in Major Lipid Variables at Final Visit (24 Week Study)

	Metformin Hydrochloride Tablets	Metformin Hydrochloride Extended-Release Tablets
	500 mg Twice Daily	1000 mg Once Daily	1500 mg Once Daily
Total Cholesterol (mg/dL)	(n = 68)	(n = 70)	(n = 66)
Baseline	199.0	201.9	201.6
Mean % Change at FINAL VISIT	0.1%	1.3%	0.1%
Total Triglycerides (mg/dL)	(n = 68)	(n = 70)	(n = 66)
Baseline	178.0	169.2	206.8
Mean % Change at FINAL VISIT	6.3%	25.3%	33.4%
LDL-Cholesterol (mg/dL)	(n = 68)	(n = 70)	(n = 66)
Baseline	122.1	126.2	115.7
Mean % Change at FINAL VISIT	–1.3%	–3.3%	–3.7%
HDL-Cholesterol (mg/dL)	(n = 68)	(n = 70)	(n = 65)
Baseline	41.9	41.7	44.6
Mean % Change at FINAL VISIT	4.8%	1.0%	–2.1%

Pediatric Clinical Studies

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 hydrochloride tablets (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 10).

Table 10: Metformin Hydrochloride Tablets vs Placebo (PediatricsPediatric patients mean age 13.8 years (range 10 to 16 years)) Summary of Mean Changes From BaselineAll patients on diet therapy at Baseline in Plasma Glucose and Body Weight at Final Visit

	Metformin Hydrochloride Tablets	Placebo	p-Value
FPG (mg/dL)	(n = 37)	(n = 36)
Baseline	162.4	192.3
Change at FINAL VISIT	–42.9	21.4	< 0.001
Body Weight (lbs)	(n = 39)	(n = 38)
Baseline	205.3	189.0
Change at FINAL VISIT	–3.3	–2.0	NSNot statistically significant

General

• Lactic acidosis—There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride extended-release tablets. In metformin hydrochloride extended-release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
• Renal impairment—The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include (see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY):
  • Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR)
  • Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² (see CONTRAINDICATIONS).
  • Initiation of metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m².
  • Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy.
• Drug interactions—The concomitant use of metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
• Age 65 or greater—The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
• Radiologic studies with contrast—Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal function is stable.
• Surgery and other procedures—Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
• Hypoxic states—Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended-release tablets.
• Excessive 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 hydrochloride extended-release tablets.
• Hepatic impairment—Patients with hepatic impairment have developed cases of metformin- associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B₁₂ levels—In controlled clinical trials of metformin hydrochloride 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 hydrochloride tablets or vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended-release tablets 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 2-to 3-year intervals may be useful.

Hypoglycemia—Hypoglycemia does not occur in patients receiving metformin hydrochloride extended-release tablets 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.

Macrovascular outcomes—There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets or any other antidiabetic drug.

Information for Patients

Patients should be informed of the potential risks and benefits of metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets, 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 counseled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride extended-release tablets.

Metformin hydrochloride extended-release tablets alone do not usually cause hypoglycemia, although it may occur when metformin hydrochloride extended-release tablets are 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).

Patients should be informed that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

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 hydrochloride tablet therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation of metformin hydrochloride extended-release tablets may be required until renal function has been confirmed to be normal (see 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 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.

Drugs that reduce metformin clearance—Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. 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.

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 sulfonylureas, which are extensively bound to serum proteins.

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, 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, the patient should be observed closely for hypoglycemia.

Carbonic anhydrase inhibitors—Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.

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 4 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 3 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 hydrochloride extended-release tablets 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. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 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 are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and effectiveness of metformin hydrochloride tablets 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 hydrochloride tablets in this age group is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 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).

Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.

Geriatric Use

Controlled clinical studies of metformin hydrochloride tablets and metformin hydrochloride extended-release 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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).