METFORMIN HYDROCHLORIDE tablet film coated

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

Buy It Now

Active ingredient:
METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N)
Available from:
REMEDYREPACK INC.
INN (International Name):
METFORMIN HYDROCHLORIDE
Composition:
METFORMIN HYDROCHLORIDE 500 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, film coated

REMEDYREPACK INC.

----------

DESCRIPTION

Metformin hydrochloride tablets, USP are an oral antihyperglycemic drug used in the management of

type 2 diabetes. Metformin hydrochloride (1,1-Dimethylbiguanide monohydrochloride) is not

chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The

structural formula is as shown:

Metformin hydrochloride, USP is a white to off-white crystalline powder with a molecular formula of

HCl and a molecular weight of 165.62. 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 tablets contain 500 mg, 850 mg or 1000 mg of metformin hydrochloride.

Each tablet contains the following inactive ingredients: artificial blackberry flavor, magnesium stearate,

polyethylene glycol, polyvinyl alcohol, povidone, talc and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2

diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action

are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic

glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by

increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce

hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special

circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy,

insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response

may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions

is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500

mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with

increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food

decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a

40% lower mean peak plasma concentration (C

), a 25% lower area under the plasma concentration

vs time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T

following administration of a single 850 mg tablet of metformin with food, compared to the same tablet

strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

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

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 µg/mL. During controlled clinical trials of metformin hydrochloride

tablets, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in

the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor

biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine

clearance, which indicates that tubular secretion is the major route of metformin elimination. Following

oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the

first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination

half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of

distribution.

Special Populations

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose

pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1),

nor is there any accumulation of metformin in either group at usual clinical doses.

Renal Impairment

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).

Hepatic Impairment

No pharmacokinetic 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 C

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

C

(µg/mL)

T

(hrs )

Renal Clearance

(mL/min)

max

max

Metformin

Hydrochloride Tablet

Dose

(number of subjects)

(µg/mL)

(hrs )

(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)

1.60 (± 0.38)

2.64 (± 0.82)

552 (± 139)

850 mg three times daily

for 19 doses

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

1.90 (± 0.62)

2.01 (± 1.22)

550 (± 160)

Elderly , 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

61 to 90

mL/min) (5)

1.86 (± 0.52)

3.20 (± 0.45)

384 (± 122)

Moderate (CL

to 60 mL/min) (4)

4.12 (± 1.83)

3.75 (± 0.50)

108 (± 57)

Severe (CL

10 to

30 mL/min) (6)

3.93 (± 0.92)

4.01 (± 1.10)

130 (± 90)

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean

metformin C

and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16

years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal

renal function.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients

with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in

controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin

hydrochloride tablets was comparable in males and females.

Race

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

controlled clinical studies of metformin hydrochloride tablets in patients with type 2 diabetes, the

All doses given fasting except the first 18 doses of the multiple dose studies

Peak plasma concentration

Time to peak plasma concentration

Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years)

Kinetic study done following dose 19, given fasting

Elderly subjects, mean age 71 years (range 65 to 81 years)

CL cr = creatinine clearance normalized to body surface area of 1.73 m 2

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

(HbA

) 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 Baseline

in Fasting Plasma Glucose, HbA

, 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

Change at FINAL VISIT

-53.0

0.001

Hemoglobin A

(%)

Baseline

Change at FINAL VISIT

-1.4

0.001

Body Weight (lbs)

Baseline

201.0

206.0

Change at FINAL VISIT

-1.4

-2.4

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

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

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

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

*

1c

All patients on diet therapy at Baseline

Not statistically significant

1c

Metformin Hydrochloride Tablets (MET) Monotherapy: Summary of Mean Changes from

Baseline

in Fasting Plasma Glucose, HbA

, and Body Weight, at Final Visit (29-Week Study)

Comb

(n = 213)

Glyb

(n = 209)

MET

(n = 210)

p-Values

Glyb vs Comb

MET vs

Comb

MET vs

Glyb

Fasting Plasma

Glucos e

(mg/dL)

Baseline

250.5

247.5

253.9

Change at

FINAL VISIT

-63.5

13.7

-0.9

0.001

0.001

0.025

Hemoglobin A

(%)

Baseline

0.007

Change at

FINAL VISIT

-1.7

-0.4

0.001

0.001

0.001

Body Weight

(lbs )

Baseline

202.2

203.0

204.0

Change at

FINAL VISIT

-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

Choles terol

(mg/dL)

Baseline

211.0

212.3

213.1

215.6

219.6

Mean %

Change at

FINAL VISIT

Total

*

1c

All patients on glyburide, 20 mg/day, at Baseline

Not statistically significant

1c

T riglycerides

(mg/dL)

Baseline

236.1

203.5

242.5

215.0

266.1

Mean %

Change at

FINAL VISIT

-16%

LDL-

Choles terol

(mg/dL)

Baseline

135.4

138.5

134.3

136.0

137.5

Mean %

Change at

FINAL VISIT

HDL-

Choles terol

(mg/dL)

Baseline

39.0

40.5

37.2

39.0

37.0

Mean %

Change at

FINAL VISIT

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 vs

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

of 2.10%, compared to a 1.56%

reduction in HbA

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 vs 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

and Daily Insulin Dose

Metformin

Hydrochloride

Tablets/Insulin

n = 26

Placebo/Insulin

n = 28

Treatment Difference

Mean ± SE

Hemoglobin A

(%)

Baseline

8.95

9.32

Change at FINAL

VISIT

-2.10

-1.56

-0.54 ± 0.43

Insulin Dose (U/day)

Baseline

93.12

94.64

Change at FINAL

VISIT

-0.15

15.93

-16.08 ± 7.77

1c

Statistically significant using analysis of covariance with baseline as covariate (p = 0.04 ) Not significant using

analysis of variance (values shown in table)

Statistically significant for insulin (p = 0.04 )

1c

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

of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets maintained similar glycemic control

(HbA

7.15 ± 0.61 vs 6.97 ± 0.62 for metformin hydrochloride tablets plus insulin and placebo plus

insulin, respectively) with 19% less insulin vs 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.

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 (Pediatrics

) Summary of Mean

Changes from 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

INDICATIONS AND USAGE

Metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic

control in adults and children with type 2 diabetes mellitus.

CONTRAINDICATIONS

Metformin hydrochloride tablets are contraindicated in patients with:

1. Severe renal impairment (eGFR below 30 mL/min/1.73 m

) (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.

WARNINGS

WARNING: LACTIC ACIDOSIS

*

Pediatric patients mean age 13.8 years (range 10 to 16 years)

All patients on diet therapy at Baseline

Not statistically significant

Postmarketing cases of metformin-associated lactic acidosis have resulted in death,

hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated

lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise,

myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic

acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis

(without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin

plasma levels generally > 5 µg/mL (see PRECAUTIONS).

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of

certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater,

having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute

congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups

are provided (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and

PRECAUTIONS).

If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride

tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is

recommended (see PRECAUTIONS).

PRECAUTIONS

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 µg/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 tablets. In metformin hydrochloride tablet-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 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 tablets, obtain an estimated glomerular filtration rate

(eGFR).

Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30

mL/min/1.73 m

(see CONTRAINDICATIONS).

Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between

30 to 45 mL/min/1.73 m

Obtain an eGFR at least annually in all patients taking metformin hydrochloride 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 tablets whose eGFR falls below 45 mL/min/1.73 m

assess the benefit and risk of continuing therapy.

Drug Interactions – The concomitant use of metformin hydrochloride 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 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 m

; 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 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 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

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 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 tablets in patients with clinical or

laboratory evidence of hepatic disease.

Vitamin B

Levels

In controlled clinical trials of metformin hydrochloride tablets of 29 weeks duration, a decrease to

subnormal levels of previously normal serum vitamin B

levels, without clinical manifestations, was

observed in approximately 7% of patients. Such decrease, possibly due to interference with B

absorption from the B

-intrinsic factor complex, is, however, very rarely associated with anemia and

12

appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B

supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on

metformin hydrochloride 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.

Hypoglycemia

Hypoglycemia does not occur in patients receiving metformin hydrochloride 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 tablets or any other antidiabetic drug.

Information for Patients

Patients should be informed of the potential risks and benefits of metformin hydrochloride 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 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 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 tablets.

Metformin hydrochloride tablets alone do not usually cause hypoglycemia, although it may occur when

metformin hydrochloride 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.)

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 B

deficiency should be excluded.

Instruct patients to inform their doctor that they are taking metformin hydrochloride tablets prior to any

surgical or radiological procedure, as temporary discontinuation of metformin hydrochloride 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

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 Tablet 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

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

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.

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

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 tablets, the

patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn

from a patient receiving metformin hydrochloride 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

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 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

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 tablets

should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with metformin hydrochloride

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 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.)

Geriatric Use

Controlled clinical studies of metformin hydrochloride 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).

ADVERSE REACTIONS

In a U.S. double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes,

a total of 141 patients received metformin hydrochloride tablet therapy (up to 2550 mg per day) and 145

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

hydrochloride tablet patients, and that were more common in metformin hydrochloride tablet- than

placebo-treated patients, are listed in Table 11.

Table 11: Most Common Adverse Reactions (> 5.0%) in a Placebo-Controlled Clinical Study of

Metformin Hydrochloride Tablet Monotherapy

Adverse Reaction

Metformin Hydrochloride

Tablet Monotherapy

(n = 141)

Placebo

(n = 145)

% of Patients

Diarrhea

53.2

11.7

Nausea/Vomiting

25.5

Flatulence

12.1

*

Asthenia

Indigestion

Abdominal Discomfort

Headache

Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin

hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥ 1.0% to ≤ 5.0%

of metformin hydrochloride tablet patients and were more commonly reported with metformin

hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail

disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing,

palpitation.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with

postmarketing use of metformin.

Pediatric Patients

In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes, the

profile of adverse reactions was similar to that observed in adults.

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 tablets or any other pharmacologic agent. Dosage of metformin

hydrochloride tablets must be individualized on the basis of both effectiveness and tolerance, while not

exceeding the maximum recommended daily doses. The maximum recommended daily dose of

metformin hydrochloride tablets is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years

of age).

Metformin hydrochloride tablets should be given in divided doses with meals. Metformin

hydrochloride 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 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 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

Reactions that were more common in metformin hydrochloride tablet- than placebo-treated patients.

of effectiveness.

Short-term administration of metformin hydrochloride tablets may be sufficient during periods of

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

Recommended Dosing Schedule

Adults

The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day or 850 mg once a

day, given with meals. In general, clinically significant responses are not seen at doses below 1500 mg

per day. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks,

up to a total of 2000 mg per day, given in divided doses. The dosage of metformin hydrochloride

tablets must be individualized on the basis of both effectiveness and tolerability. Patients can also be

titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring

additional glycemic control, metformin hydrochloride tablets may be given to a maximum daily dose of

2550 mg per day. Doses above 2000 mg may be better tolerated given 3 times a day with meals.

Pediatrics

The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day, given with meals.

Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per

day, given in divided doses. The dosage of metformin hydrochloride tablets must be individualized on

the basis of both effectiveness and tolerability.

Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of metformin hydrochloride tablets and periodically thereafter.

Metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration

rate (eGFR) below 30 mL/min/1.73 m

Initiation of metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m

is not recommended.

In patients taking metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m

assess the benefit risk of continuing therapy.

Discontinue metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/min/1.73 m

(see WARNINGS and PRECAUTIONS).

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue metformin hydrochloride 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 m

; 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 tablets if renal function is stable.

Concomitant Metformin Hydrochloride Tablet and Oral Sulfonylurea Therapy in Adult Patients

If patients have not responded to 4 weeks of the maximum dose of metformin hydrochloride tablet

monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while

continuing metformin hydrochloride 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 tablet 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 mg/20 mg, 1500 mg/20 mg, 2000 mg/20 mg, or 2500 mg/20 mg

of metformin hydrochloride tablets and glyburide, respectively, to reach the goal of glycemic control

as measured by FPG, HbA

, 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 tablet 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 tablets and the maximum dose of an oral sulfonylurea, consider

therapeutic alternatives including switching to insulin with or without metformin hydrochloride tablets.

Concomitant Metformin Hydrochloride Tablet and Insulin Therapy in Adult Patients

The current insulin dose should be continued upon initiation of metformin hydrochloride tablet therapy.

Metformin hydrochloride tablet therapy should be initiated at 500 mg once daily in patients on insulin

therapy. For patients not responding adequately, the dose of metformin hydrochloride 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 2500 mg for metformin

hydrochloride 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 tablets. Further adjustment should be individualized based on

glucose-lowering response.

Specific Patient Populations

Metformin hydrochloride tablets are not recommended for use in pregnancy. Metformin hydrochloride

tablets are not recommended in patients below the age of 10 years.

The initial and maintenance dosing of metformin hydrochloride 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.

HOW SUPPLIED

Metformin Hydrochloride Tablets, USP are available containing 500 mg, 850 mg or 1000 mg of

metformin hydrochloride, USP.

The 500 mg tablets are white to off-white, film-coated, round, unscored tablets with blackberry scent

debossed with MF over 1 on one side of the tablet and G on the other side. They are available as

follows:

NDC 0378-7185-05

bottles of 500 tablets

The 850 mg tablets are white to off-white, film-coated, round, unscored tablets with blackberry scent

debossed with MF over 2 on one side of the tablet and G on the other side. They are available as

follows:

NDC 0378-7186-05

bottles of 500 tablets

The 1000 mg tablets are white to off-white, film-coated, oblong, scored tablets with blackberry scent

debossed with MF to the left side of the score and 3 to the right side of the score on one side of the

tablet and G to the left side of the score and G to the right side of the score on the other side. They are

available as follows:

NDC 0378-7187-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Patient Information

Metformin Hydrochloride Tablets, USP

(met for′ min hye″ droe klor′ ide)

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 are metformin hydrochloride tablets?

Metformin hydrochloride tablets are 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 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.

This medicine helps 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 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.

Tell your doctor if you are pregnant or plan to become pregnant. Metformin hydrochloride 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 tablets be used in children?

Metformin hydrochloride tablets have been shown to effectively lower glucose levels in children (ages

10 to 16 years) with type 2 diabetes. Metformin hydrochloride tablets have not been studied in children

younger than 10 years old. Metformin hydrochloride tablets have not been studied in combination with

other oral glucose-control medicines or insulin in children. If you have any questions about the use of

metformin hydrochloride tablets in children, talk with your doctor or healthcare provider.

How should I take metformin hydrochloride 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 tablets with meals.

Your doctor may have you take other medicines along with metformin hydrochloride tablets to control

your blood sugar. These medicines may include insulin shots. Taking metformin hydrochloride 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 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 tablets cause 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 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 tablets for a short time.

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

can affect how well other drugs work, and some drugs can affect how well metformin

hydrochloride tablets work. Some medicines may cause high blood sugar.

What should I avoid while taking metformin hydrochloride tablets?

Do not drink a lot of alcoholic drinks while taking metformin hydrochloride 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 tablets?

Lactic acidosis. Metformin, the active ingredient in metformin hydrochloride tablets,can

cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that

can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic

acidosis:

you feel cold in your hands or feet

you feel dizzy or lightheaded

you have a slow or irregular heartbeat

you feel very weak or tired

you have unusual (not normal) muscle pain

you have trouble breathing

you feel sleepy or drowsy

you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with the

metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you

have a higher chance for getting lactic acidosis with metformin hydrochloride tablets if you:

have severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable

have liver problems

drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking

get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever,

vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise

and do not drink enough fluids

have surgery

have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor

if you have any of the problems in the list above. Your doctor may decide to stop your metformin

hydrochloride tablets for a while if you have any of these things.

Other Side Effects. Common side effects of metformin hydrochloride 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 tablets have an unpleasant metallic

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

Metformin hydrochloride 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.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

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 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 tablets for a condition for which they

were not prescribed. Do not share your medicine with other people.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Manufactured by:

Mylan Laboratories Limited

Hyderabad — 500 034, India

Code No.: MH/DRUGS/25/NKD/89

75058725

Revised: 5/2017

MX:METB:R4pt/MX:PL:METB:R4pt

DRUG: Metformin Hydrochloride

GENERIC: metformin hydrochloride

DOSAGE: TABLET, FILM COATED

ADMINSTRATION: ORAL

NDC: 61786-974-02

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 11 mm

IMPRINT: MF;1;G

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

METFORMIN HYDROCHLORIDE 500mg in 1

INACTIVE INGREDIENT(S):

BLACKBERRY

POVIDONE, UNSPECIFIED

TALC

POLYVINYL ALCOHOL, UNSPECIFIED

MAGNESIUM STEARATE

POLYETHYLENE GLYCOL, UNSPECIFIED

TITANIUM DIOXIDE

METFORMIN HYDROCHLORIDE

metformin hydrochloride tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 178 6 -9 74(NDC:0 378 -718 5)

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

REMEDYREPACK INC.

Inactive Ingredients

Ingredient Name

Stre ng th

BLACKBERRY (UNII: 8 A6 OMU3I8 L)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

white (white to o ff-white)

S core

no sco re

S hap e

ROUND

S iz e

11mm

Flavor

Imprint Code

MF;1;G

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:6 178 6 -9 74-

30 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

11/0 8 /20 16

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 759 73

11/0 8 /20 16

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 10/2017

Similar products

Search alerts related to this product

Share this information