Metformin Hydrochloride Extended-Release

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.

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 tablets 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.

 Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 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.

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.

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

Renal Impairment

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 also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

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

Geriatrics

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 Cmax 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). Metformin hydrochloride extended-release 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 (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of  Metformin  Hydrochloride Tablets
Subject Groups: Metformin Hydrochloride Tablet dose a (number of subjects)	Cmax b    (mcg/mL)	Tmax c     (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)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 dosese  (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 (CL cr g 61-90 mL/min) (5)	1.86 (±0.52)	3.20 (±0.45)	384 (±122)
Moderate (CL cr 31-60 mL/min) (4)	4.12 (±1.83)	3.75 (±0.50)	108 (±57)
Severe (CL cr 10-30 mL/min) (6)	3.93 (±0.92)	4.01 (±1.10)	130 (±90)

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  m ²

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).
Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

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 (HbA1c 7 to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8% 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% but <8% (patients with HbA _1c ≥8% 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 to 11%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 2.

Table 2:Sum mary of Mean Ch a nges f rom Baseline* in Hb A1c, 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
H e m og l o bi n A1c (%) Baseline Change at FINAL VISIT    p-value a	( n= 115) 8.2      -0.4      <0.001	( n= 115) 8.4 -0.6    <0.001	( n= 111) 8.3 -0.9    <0.001	( n= 125) 8.4 -0.8   <0.001	( n= 112) 8.4 -1.1   <0.001	( n= 111)      8.4      0.1          -
FP G (mg/dL) Baseline Change at FINAL VISIT   p-value a	( n= 126)     182.7      -15.2      <0.001	( n= 118)      183.7 -19.3  <0.001	( n= 120)      178.9 -28.5  <0.001	( n= 132) 181 -29.9 <0.001	( n= 122)      181.6       -33.6 <0.001	( n= 113)     179.6 7.6 -
Bo dy Weight (lbs) Baseline Change at FINAL VISIT     p-value a	( n= 125)     192.9   -1.3  NS**	( n= 119)      191.8   -1.3   NS**	( n= 117)      188.3  -0.7       NS**	( n= 131)      195.4  -1.5         NS**	( n= 119)      192.5  -2.2   NS**	( n= 113)      194.3  -1.8  -

*All patients on diet therapy at Baseline

^a All comparisons versus Placebo

**Not statistically significant

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 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 500 mg twice daily for at least 8 weeks prior to study entry.

The metformin hydrochloride 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 3 . 

Table3:          Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study)
	Metformin Hydrochloride Tablets 500 mg  Twice Daily	Metformin Hydrochloride Extended-Release Tablets
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	0.14 a	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	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	11.5	7.6
(95% CI)	(7, 21)	(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)	(-0.4, 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)

*   All patients on metformin hydrochloride tablets 500 mg twice daily at Baseline

a n=68

 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 4.

T able 4:Summary of Mean Percent Changes from 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
T o tal Cholesterol (mg/dL)    Baseline    Mean % Change at FINAL    VISIT	( n= 120) 210.3 1%	( n= 113) 218.1 1.7%	( n= 110) 214.6 0.7%	( n= 126) 204.4 -1.6%	( n= 117) 208.2 -2.6%	( n= 110) 208.6 -2.6%
T o tal Triglyceides (mg/dL)    Baseline    Mean % Change at FINAL    VISIT	( n= 120) 220.2 14.5%	( n= 113) 211.9 9.4%	( n= 110) 198 15.1%	( n= 126) 194.2 14.9%	( n= 117) 179 9.4%	( n= 110) 211.7 10.9%
LDL   Cholesterol (mg/dL)    Baseline    Mean % Change at FINAL    VISIT	( n= 119) 131 -1.4%	( n= 113) 134.9 -1.6%	( n= 109) 135.8 -3.5%	( n= 126) 125.8 -3.3%	( n= 117) 131.4 -5.5%	( n= 107) 131.9 -3.2%
HDL   Cholesterol (mg/dL)    Baseline    Mean % Change at FINAL    VISIT	( n= 120) 40.8 6.2%	( n= 108) 41.6 8.6%	( n= 108) 40.6 5.5%	( n= 125) 40.2 6.1%	( n= 117) 42.4 7.1%	( n= 108) 39.4 5.8%

*All patients on diet therapy at Baseline

Changes in lipid parameters in the previously described study of metformin hydrochloride tablets and metformin hydrochloride extended-release tablets are shown in Table 5.

Table 5:                        Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24 week study)
	Metformin Hydrochloride Tablets  500 mg Twice Daily	Metformin Hydrochloride Extended-Release Tablets
1000 mg Once Daily	1500 mg Once Daily
Total Cholesterol (mg/dL)	(n=68)	(n=70)	(n=66)
Baseline	199	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	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 FINALVISIT	4.8%	1%	-2.1%

*All patients on metformin hydrochloride tablets  500 mg twice daily at baseline

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 Cmax 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 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.

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. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride extended-release tablets 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, 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.

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.

Adults
In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of metformin hydrochloride extended-release tablets, USP is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on metformin hydrochloride extended-release tablets, USP 2000 mg once daily, a trial of metformin hydrochloride extended-release tablets, USP 1000 mg twice daily should be considered. (See CLINICAL PHARMACOLOGY : Clinical Studies .)

In a randomized trial, patients currently treated with metformin hydrochloride tablets were switched to metformin hydrochloride extended-release tablets. Results of this trial suggest that patients receiving metformin hydrochloride tablets treatment may be safely switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin hydrochloride tablets to metformin hydrochloride extended-release tablets, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY : Clinical Studies ).

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

Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter.
Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.
Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended.
In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
Discontinue metformin hydrochloride extended-release tablets if the patients eGFR later falls below 30 mL/minute/1.73 m2 (See  WARNINGS and PRECAUTIONS).

Discontinue 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 liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable.

If patients have not responded to 4 weeks of the maximum dose of metformin hydrochloride extended-release tablets monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride extended-release tablets, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug- drug interaction data are currently available only for metformin plus glyburide (glibenclamide).

With concomitant metformin hydrochloride extended-release tablets and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin hydrochloride tablets 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride tablets and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response (see CLINICAL PHARMACOLOGY : Clinical Studies ). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin hydrochloride extended-release tablets, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)

If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of metformin hydrochloride extended-release tabletsand the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride extended-release tablets.

The current insulin dose should be continued upon initiation of metformin hydrochloride extended-release tablets therapy. Metformin hydrochloride extended-release tablets therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride extended-release tablets should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2000 mg for metformin hydrochloride extended-release tablets. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin hydrochloride extended-release tablets, USP. Further adjustment should be individualized based on glucose-lowering response.

Metformin hydrochloride extended-release tablets is not recommended for use in pregnancy. Metformin hydrochloride extended-release tablets, USP is not recommended in pediatric patients (below the age of 17 years).

The initial and maintenance dosing of metformin hydrochloride extended-release tablets should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin hydrochloride extended-release tablets.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS .)