METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N)
Available from:
Nostrum Laboratories Inc.
INN (International Name):
metformin hydrochloride
Composition:
metformin hydrochloride 500 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Metformin hydrochloride extended-release tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Metformin hydrochloride extended-release tablets are contraindicated in patients with: - Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS ). - Known hypersensitivity to metformin hydrochloride. - Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. Metformin hydrochloride extended-release tablets 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 al
Product summary:
Metformin Hydrochloride Extended-Release Tablets, USP 500 mg are white, uncoated, oblong tablets, debossed with "NM5" Metformin Hydrochloride Extended-Release Tablets, USP 750 mg are white, uncoated, oblong tablets, debossed with"NM7" Store at 20°–25° C (68°–77° F); excursions permitted to 15°–30° C (59°–86° F). [See USP Controlled Room Temperature.] “Dispense in tight light-resistant containers” in accordance with the USP requirements for this drug product.
Authorization status:
Abbreviated New Drug Application
Authorization number:
29033-018-01, 29033-018-05, 29033-018-10, 29033-021-01, 29033-021-10

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, extended release

Nostrum Laboratories Inc.

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Metformin Hydrochloride Extended-Release Tablets, USP

DESCRIPTION

Metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic drugs used in the

management of type 2 diabetes. Metformin hydrochloride ( 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 hydrochloride is a white to off-white crystalline compound with a molecular formula of C

HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water

and is practically insoluble in acetone, ether, and chloroform. The pK

of metformin is 12.4. The pH of

a 1% aqueous solution of metformin hydrochloride is 6.68.

Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin

hydrochloride as the active ingredient. Each tablet contains the inactive ingredients hypromellose,

silicified microcrystalline cellulose, xanthan gum, maltodextrin, colloidal silicon dioxide and stearic

acid.

Dissolution Method: USP dissolution test is pending.

System Components and Performance - Metformin hydrochloride extended-release tablets, USP

comprises a drug releasing polymer. After administration, fluid from the gastrointestinal (GI) tract

enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage

form by a process of diffusion through the gel matrix that is essentially independent of pH. The

hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI

tract. The biologically inert components of the tablet may occasionally remain intact during GI transit

and will be eliminated in the feces as a soft, hydrated mass.

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

Following a single oral dose of Metformin hydrochloride extended-release tablets, C

is achieved

with a median value of 7 hours and a range of 4 to 8 hours.

At steady state, the AUC and C

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 µg/mL for 500, 1000, 1500, and 2000 mg once-daily

doses, respectively. After repeated administration of Metformin hydrochloride extended-release

tablets, metformin did not accumulate in plasma.

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

and T

of metformin. Both high and low fat meals had the same effect on the

pharmacokinetics of Metformin hydrochloride extended-release tablets.

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 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, 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.

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 WARNINGS).

Hepatic Insufficiency

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

Geriatrics

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).

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

Race

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

Clinical Studies

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

7.0%-10.0%, FPG 126-270 mg/dL).

Patients entering the study had a mean baseline HbA

of 8.0% and a mean baseline FPG of 176 mg/dL.

After 12 weeks treatment, mean HbA

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

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

was ≥7.0% but <8.0%

(patients with HbA

≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA

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

7.0%-11.0%, FPG 126-280 mg/dL). Changes in

glycemic control and body weight are shown in Table 6.

Table 6: Summary of Mean Changes from Baseline* in HbA

, 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

* All patients on diet therapy at Baseline

All comparisons versus Placebo

** Not statistically significant

Hemoglobin A

(%)

(n=115)

(n=115)

(n=111)

(n=125)

(n=112)

(n=111)

Baseline

Change at FINAL VISIT

–0.4

–0.6

–0.9

–0.8

–1.1

p-value

<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

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

NS**

NS**

NS**

NS**

NS**

1c

1c

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, 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

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 Baseline in HbA

, Fasting Plasma Glucose, and

Body Weight at Week 12 and at Final Visit (24-week study)

Metformin hydrochloride extended-release tablets

1000 mg

Once Daily

1500 mg

Once Daily

Hemoglobin A

(%)

(n=72)

(n=66)

Baseline

6.99

7.02

Change at 12 Weeks

0.23

0.04

(95% CI)

(0.1, 0.36)

(–0.08, 0.15)

Change at FINAL VISIT

0.27

0.13

(95% CI)

(0.11, 0.43)

(–0.02, 0.28)

FPG (mg/dL)

(n=72)

(n=70)

Baseline

131.4

Change at 12 Weeks

(95% CI)

(4.4, 14.6)

(–0.4, 7.8)

Change at FINAL VISIT

11.5

(95% CI)

(4.4, 18.6)

(1, 14.2)

Body Weight (lbs)

(n=74)

(n=71)

Baseline

202.8

192.7

Change at 12 Weeks

(95% CI)

(0, 2)

(–0.4, 1.8)

Change at FINAL VISIT

(95% CI)

(–0.2, 2.4)

(–0.4, 2)

After 12 weeks of treatment, there was an increase in mean HbA

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 Baseline* in Major Lipid Variables at Final

Visit (16-week study)

Metformin HCl Extended-Release Tablets

500 mg

1000 mg 1500 mg 2000 mg 1000 mg

1c

1c

500 mg

Once

Daily

1000 mg

Once

Daily

1500 mg

Once

Daily

2000 mg

Once

Daily

1000 mg

Twice

Daily

Placebo

* All patients on diet therapy at Baseline

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

1.7%

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

194.2

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

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 extended-

release tablets, USP are shown in Table 9.

Table 9: Summary of Mean Percent Changes from Baseline in Major Lipid Variables at Final

Visit (24-week study)

Metformin HCl extended-release tablets

1000 mg

Once Daily

1500 mg

Once Daily

Total Cholesterol (mg/dL)

(n=70)

(n=66)

Baseline

201.9

201.6

Mean % Change at FINAL VISIT

1.3%

0.1%

Total Triglycerides (mg/dL)

(n=70)

(n=66)

Baseline

169.2

206.8

Mean % Change at FINAL VISIT

25.3%

33.4%

LDL-Cholesterol (mg/dL)

(n=70)

(n=66)

Baseline

126.2

115.7

Mean % Change at FINAL VISIT

−3.3%

−3.7%

HDL-Cholesterol (mg/dL)

(n=70)

(n=65)

Baseline

41.7

44.6

Mean % Change at FINAL VISIT

1.0%

–2.1%

INDICATIONS AND USAGE

Metformin hydrochloride extended-release tablets, USP is indicated as an adjunct to diet and exercise to

improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS

Metformin hydrochloride extended-release tablets are 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 hydrochloride.

3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

Diabetic ketoacidosis should be treated with insulin.

Metformin hydrochloride extended-release tablets 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 hydrochloride extended-release

tablets 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

hydrochloride extended release tablets and by use of the minimum effective dose of

Metformin hydrochloride extended release tablets. In particular, treatment of the elderly

should be accompanied by careful monitoring of renal function. 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, as

these patients are more susceptible to developing lactic acidosis. In addition, Metformin

hydrochloride extended release tablets 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 hydrochloride

extended release tablets 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 hydrochloride extended release tablets,

since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In

addition, Metformin hydrochloride extended release tablets 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

hydrochloride extended release tablets 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 hydrochloride extended release tablets, 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 hydrochloride extended release tablets 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 hydrochloride extended release tablets, the

drug should be discontinued immediately and general supportive measures promptly

instituted. Because metformin hydrochloride 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 hydrochloride extended release tablets or any other

antidiabetic 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 hydrochloride extended release tablets. In patients with advanced age,

Metformin hydrochloride extended release tablets 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 hydrochloride extended release tablets should not be titrated to the maximum dose

(see WARNINGS and DOSAGE AND ADMINISTRATION).

Before initiation of Metformin hydrochloride extended-release tablets 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

hydrochloride extended-release tablets 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

hydrochloride extended-release tablets 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

hydrochloride extended-release tablets therapy, the drug should be promptly discontinued.

Surgical procedures—Metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets.

Impaired hepatic function—Since impaired hepatic function has been associated with some cases of

lactic acidosis, Metformin hydrochloride extended-release tablets should generally be avoided in

patients with clinical or laboratory evidence of hepatic disease.

Vitamin B

levels —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 B

or calcium intake or absorption) appear to be

predisposed to developing subnormal vitamin B

levels. In these patients, routine serum vitamin B

measurements at 2- to 3-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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets

must be stopped immediately and other appropriate corrective measures initiated (see also

WARNINGS).

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.

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 hydrochloride extended-release tablets and

temporarily administer insulin. Metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets or sulfonylurea

monotherapy, combined therapy with Metformin hydrochloride extended-release tablets and

sulfonylurea may result in a response. Should secondary failure occur with combined Metformin

hydrochloride extended-release tablets/sulfonylurea therapy, it may be necessary to consider

therapeutic alternatives including initiation of insulin therapy.

12

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 counselled against excessive alcohol intake, either acute or chronic, while receiving

Metformin hydrochloride extended-release tablets.

Metformin hydrochloride extended-release tablets alone does not usually cause hypoglycemia,

although it may occur when Metformin hydrochloride extended-release tablets 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.)

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.

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

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

by 22% and blood AUC by 15%, without

any significant change in metformin renal clearance. When administered with metformin, the C

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

and AUC by 20%

and 9%, respectively, and increased the amount excreted in the urine. T

and half-life were

unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects

on nifedipine.

Cationic drugs—Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine,

ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion

theoretically have the potential for interaction with metformin by competing for common renal tubular

transport systems. Such interaction between metformin and oral cimetidine has been observed in normal

healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with

a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma

and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study.

Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical

(except for cimetidine), careful patient monitoring and dose adjustment of Metformin hydrochloride

extended-release tablets, USP and/or the interfering drug is recommended in patients who are taking

cationic medications that are excreted via the proximal renal tubular secretory system.

Other—Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These

drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,

estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking

drugs, and isoniazid. When such drugs are administered to a patient receiving Metformin hydrochloride

extended-release tablets, 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.

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.

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

Teratogenic Effects: Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are

associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be

used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal

reproduction studies are not always predictive of human response, Metformin hydrochloride 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 two and six times the maximum recommended human

daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively.

Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to

those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for

hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or

to discontinue the drug, taking into account the importance of the drug to the mother. If Metformin

hydrochloride extended-release tablet is discontinued, and if diet alone is inadequate for controlling

blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness of Metformin hydrochloride extended-release tablets in pediatric patients have

not been established.

Geriatric Use

Controlled clinical studies of 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. 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 hydrochloride extended-release tablets 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

hydrochloride extendedrelease tablets 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 hydrochloride

extended-release tablets (see also WARNINGS and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with Metformin

hydrochloride extended-release tablets, USP in placebo- and active-controlled studies. In placebo-

controlled trials, 781 patients were administered Metformin hydrochloride extended-release tablets and

195 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin

hydrochloride extended-release tablets patients, and that were more common in Metformin

hydrochloride extended-release tablets, than placebo-treated patients, are listed in Table 12.

Table 12: Most Common Adverse Reactions (>5.0 Percent) in Placebo-Controlled Studies of

Metformin HCl Extended-release tablets*

Adverse Reaction

Metformin hydrochloride

extended-release tablets

(n=781)

Placebo

(n=195)

% of Patients

* Reactions that were more common in Metformin hydrochloride extended release tablets- than

placebo-treated patients.

Diarrhea

Nausea/Vomiting

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Metformin

hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in

≥1.0% to ≤5.0% of Metformin hydrochloride extended-release tablets patients and were more

commonly reported with Metformin hydrochloride extended-release tablets than placebo: abdominal

pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper

respiratory infection, taste disturbance.

OVERDOSAGE

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50

grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with

metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32%

of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170

mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of

accumulated drug from patients in whom metformin overdosage is suspected.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes

with Metformin hydrochloride extended release tablets or any other pharmacologic agent. Dosage of

Metformin hydrochloride extended release tablets must be individualized on the basis of both

effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum

daily dose of metformin hydrochloride extended-release tablets in adults is 2000 mg.

Metformin hydrochloride extended-release tablets should generally be given once daily with the

evening meal. Metformin hydrochloride extended-release tablets should be started at a low dose, with

gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the

minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma

glucose should be used to determine the therapeutic response to Metformin hydrochloride extended-

release tablets and identify the minimum effective dose for the patient. Thereafter, glycosylated

hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should

be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near

normal by using the lowest effective dose of Metformin hydrochloride extended-release tablets

either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary

failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication,

and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period

of effectiveness.

Short-term administration of Metformin hydrochloride extended-release tablets may be sufficient during

periods of transient loss of control in patients usually well-controlled on diet alone.

Metformin hydrochloride extended release tablets must be swallowed whole and never crushed

or chewed. Occasionally, the inactive ingredients of Metformin hydrochloride extended release tablets

will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)

Recommended Dosing Schedule

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 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 2000 mg once daily, a trial of Metformin

hydrochloride extended- release tablets 1000 mg twice daily should be considered. (See CLINICAL

PHARMACOLOGY: Clinical Studies.)

Pediatrics

Safety and effectiveness of Metformin hydrochloride extended release tablets in pediatric patients have

not been established.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to

Metformin hydrochloride extended-release tablets no transition period generally is necessary. When

transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because

of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and

possible hypoglycemia.

Concomitant Metformin hydrochloride extended-release tablets and Oral Sulfonylurea Therapy

in Adult Patients

If patients have not responded to four 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 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.With concomitant

Metformin hydrochloride extended-release tablets 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 one to three months of concomitant therapy with the

maximum dose of Metformin hydrochloride extended-release tablets and the maximum dose of an oral

sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin

hydrochloride extended-release tablets.

Concomitant Metformin hydrochloride extended-release tablets, USP and Insulin Therapy in

Adult Patients

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. Further adjustment should be individualized based on glucose-

hydrochloride extended-release tablets. Further adjustment should be individualized based on glucose-

lowering response.

Specific Patient Populations

Metformin hydrochloride extended-release tablets are not recommended for use in pregnancy or 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.)

HOW SUPPLIED

Metformin Hydrochloride Extended-Release Tablets, USP 500 mg are white, uncoated, oblong tablets,

debossed with "NM5"

Bottles of 100

NDC 29033-018-01

Bottles of 500

NDC 29033-018-05

Bottles of 1000

NDC 29033-018-10

Metformin Hydrochloride Extended-Release Tablets, USP 750 mg are white, uncoated, oblong tablets,

debossed with"NM7"

Bottles of 100

NDC 29033-021-01

Bottles of 1000

NDC 29033-021-10

Storage

Store at 20°–25° C (68°–77° F); excursions permitted to 15°–30° C (59°–86° F). [See USP Controlled

Room Temperature.]

“Dispense in tight light-resistant containers” in accordance with the USP requirements for this drug

product.

Manufactured by:

Nostrum Laboratories Inc.

1800 N Topping Avenue

Kansas City, MO 64120

Revised: November 2011

Patient Information

Metformin Hydrochloride Extended-Release Tablets

Read this information carefully before you start taking this medicine and each time you refill your

prescription. There may be new information. This information does not take the place of your doctor’s

advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want

to know more about this medicine.

What is Metformin hydrochloride extended-release tablets?

Metformin hydrochloride extended-release tablets is used to treat type 2 diabetes. This is also known as

non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin

or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in

the blood. This can lead to serious medical problems including kidney damage, amputations, and

blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to

lower your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by

insulin shots. Before you take Metformin hydrochloride extended-release tablets try to control your

diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and

follow the diet advised for your diabetes. No matter what your recommended diabetes management plan

is, studies have shown that maintaining good blood sugar control can prevent or delay complications of

diabetes, such as blindness.

Metformin hydrochloride extended-release tablets works longer in your body. Metformin

hydrochloride extended-release tablets help control your blood sugar in a number of ways. These

include helping your body respond better to the insulin it makes naturally, decreasing the amount of

sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin

hydrochloride extended-release tablets do not cause your body to make more insulin. Because of this,

when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight

gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to

occur, as is weight gain.

WARNING: Most people with kidney problems should not take Metformin hydrochloride

extended-release tablets. (See "What are the side effects of Metformin hydrochloride extended-

release tablets?")

Who should not take Metformin hydrochloride extended-release tablets?

Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take

either of these medicines. Most of the conditions listed below can increase your chance of getting

lactic acidosis.

Do not take Metformin hydrochloride extended-release tablets if you:

have kidney problems

have liver problems

have heart failure that is treated with medicines, such as Lanoxin

(digoxin) or Lasix

(furosemide)

drink a lot of alcohol. This means you binge drink for short periods or drink all the time

are seriously dehydrated (have lost a lot of water from your body)

are going to have an x-ray procedure with injection of dyes (contrast agents)

are going to have surgery

develop a serious condition, such as heart attack, severe infection, or a stroke

are 80 years or older and you have NOT had your kidney function tested

Tell your doctor if you are pregnant or plan to become pregnant. Metformin hydrochloride extended-

release tablets may not be right for you. Talk with your doctor about your choices. You should also

discuss your choices with your doctor if you are nursing a child.

Can Metformin hydrochloride extended-release tablets be used in children?

Metformin hydrochloride extended-release tablet has not been studied in children.

How should I take Metformin hydrochloride extended-release tablets?

How should I take Metformin hydrochloride extended-release tablets?

Your doctor will tell you how much medicine to take and when to take it. You will probably start out

with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is

better controlled. You should take Metformin hydrochloride extended-release tablets with meals.

Your doctor may have you take other medicines along with Metformin hydrochloride extended-release

tablets to control your blood sugar. These medicines may include insulin shots. Taking Metformin

hydrochloride extended-release tablets with insulin may help you better control your blood sugar while

reducing the insulin dose.

Continue your exercise and diet program and test your blood sugar regularly while taking Metformin

hydrochloride extended-release tablets. Your doctor will monitor your diabetes and may perform blood

tests on you from time to time to make sure your kidneys and your liver are functioning normally. There

is no evidence that Metformin hydrochloride extended-release tablets causes harm to the liver or

kidneys.

Tell your doctor if you:

have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount

of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body).

You may need to stop taking Metformin hydrochloride extended-release tablets for a short time.

plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to

stop taking Metformin hydrochloride extended release tablets for a short time.

start to take other medicines or change how you take a medicine. Metformin hydrochloride extended

release tablets can affect how well other drugs work, and some drugs can affect how well

Metformin hydrochloride extended release tablets work. Some medicines may cause high blood

sugar.

Metformin hydrochloride extended release tablets must be swallowed whole and never crushed

or chewed. Occasionally, the inactive ingredients of Metformin hydrochloride extended-release tablets

may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful

and will not affect the way Metformin hydrochloride extended-release tablets works to control your

diabetes.

What should I avoid while taking Metformin hydrochloride extended-release tablets?

Do not drink a lot of alcoholic drinks while taking Metformin hydrochloride extended-release tablets.

This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a

regular basis. Alcohol can increase the chance of getting lactic acidosis.

What are the side effects of Metformin hydrochloride extended-release tablets?

Lactic Acidosis. In rare cases, Metformin hydrochloride extended-release tablets can cause a

serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood.

This buildup can cause serious damage. Lactic acidosis caused by Metformin hydrochloride

extended-release tablets is rare and has occurred mostly in people whose kidneys were not working

normally. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who

develop it.

It is also important for your liver to be working normally when you take Metformin hydrochloride

extended-release tablets. Your liver helps remove lactic acid from your blood.

Make sure you tell your doctor before you use Metformin hydrochloride extended-release tablets if

you have kidney or liver problems. You should also stop using Metformin hydrochloride extended-

release tablets and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis

is a medical emergency that must be treated in a hospital.

Signs of lactic acidosis are:

feeling very weak, tired, or uncomfortable

unusual muscle pain

trouble breathing

unusual or unexpected stomach discomfort

feeling cold

feeling dizzy or lightheaded

suddenly developing a slow or irregular heartbeat

If your medical condition suddenly changes, stop taking Metformin hydrochloride extended-release

tablets and call your doctor right away. This may be a sign of lactic acidosis or another serious side

effect.

Other Side Effects. Common side effects of Metformin hydrochloride extended-release tablets include

diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine

for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if

the side effects bother you a lot, last for more than a few weeks, come back after they’ve gone away, or

start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period

or for good.

About 3 out of every 100 people who take Metformin hydrochloride extended-release tablets have an

unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

Metformin hydrochloride extended-release tablets rarely cause hypoglycemia (low blood sugar) by

themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if

you take other medicines to lower blood sugar.

General advice about prescription medicines

If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your

doctor or pharmacist for the information about Metformin hydrochloride extended-release tablets that is

written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those

listed in a patient information leaflet. Do not use Metformin hydrochloride extended-release tablets for

a condition for which it was not prescribed. Do not share your medicine with other people.

Manufactured By:

Nostrum Laboratories Inc.

1800 N Topping Avenue

Kansas city, MO 64120

PRINCIPAL DISPLAY PANEL

See How Supplied section for a complete list of available packages of Metformin hydrochloride

extended-release tablets, USP.

PRINCIPAL DISPLAY PANEL - 500 mg (500 Count)

NDC 29033-018-05

Metformin hydrochloride extended-release tablets USP, 500 mg

PHARMACIST: Dispense the enclosed patient information leaflet to each patient

500 Tablets Rx only

NDC 29033-021-01

METFORMIN HYDROCHLORIDE

metformin hydrochloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:29 0 33-0 18

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METFO RMIN HYDRO CHLO RIDE (UNII: 78 6 Z46 38 9 E) (METFORMIN -

UNII:9 10 0 L32L2N)

METFORMIN

HYDROCHLORIDE

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

XANTHAN GUM (UNII: TTV12P4NEE)

MALTO DEXTRIN (UNII: 7CVR7L4A2D)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

Product Characteristics

Color

white (white)

S core

no sco re

S hap e

CAPSULE (o blo ng)

S iz e

19 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:29 0 33-0 18 -0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 1/20 12

2

NDC:29 0 33-0 18 -0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 1/20 12

3

NDC:29 0 33-0 18 -10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 1/20 12

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 756

0 1/0 1/20 12

METFORMIN HYDROCHLORIDE

metformin hydrochloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:29 0 33-0 21

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METFO RMIN HYDRO CHLO RIDE (UNII: 78 6 Z46 38 9 E) (METFORMIN -

UNII:9 10 0 L32L2N)

METFORMIN

HYDROCHLORIDE

750 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

XANTHAN GUM (UNII: TTV12P4NEE)

MALTO DEXTRIN (UNII: 7CVR7L4A2D)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

Product Characteristics

Color

white (white)

S core

no sco re

S hap e

CAPSULE (o blo ng)

S iz e

19 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:29 0 33-0 21-0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 1/20 12

2

NDC:29 0 33-0 21-10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/0 1/20 12

Marketing Information

Nostrum Laboratories Inc.

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 756

0 1/0 1/20 12

Labeler -

Nostrum Laboratories Inc. (791142354)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

No strum Labo rato ries,

Inc .

79 1142354

manufacture(29 0 33-0 18 , 29 0 33-0 21) , analysis(29 0 33-0 18 , 29 0 33-0 21) , pack(29 0 33-

0 18 , 29 0 33-0 21)

Revised: 12/2018

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