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:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Metformin hydrochloride extended-release tablets are 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: - Severe renal impairment (eGFR below 30 mL/min/1.73 m2 ) [see Warnings and Precautions (5.1)] . - Hypersensitivity to metformin. - Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when me
Product summary:
Product: 63629-8166 NDC: 63629-8166-1 180 TABLET, EXTENDED RELEASE in a BOTTLE NDC: 63629-8166-2 30 TABLET, EXTENDED RELEASE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8166-1, 63629-8166-2

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, extended release

Bryant Ranch Prepack

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use METFORMIN HYDROCHLORIDE

EXTENDED-RELEASE TABLETS safely and effectively. See full prescribing information for METFORMIN

HYDROCHLORIDE EXTENDED-RELEASE TABLETS.

METFORMIN HYDROCHLORIDE extended-release tablets, for oral use

Initial U.S. Approval: 1995

WARNING: LACTIC ACIDOSIS

See full prescribing information for complete boxed warning.

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

hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory

distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate

levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally > 5

mcg/mL. (5.1)

Risk factors include renal impairment, concomitant use of certain drugs, age > 65 years old,

radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol

intake, and hepatic impairment. Steps to reduce the risk of and manage metforminassociated lactic

acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)

If lactic acidosis is suspected, discontinue metformin hydrochloride extended-release tablets and

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

(5.1)

INDICATIONS AND USAGE

Metformin hydrochloride extended-release tablets are a biguanide indicated as an adjunct to diet and exercise to improve

glycemic control in adults with type 2 diabetes mellitus. (1)

DOSAGE AND ADMINISTRATION

Adult Dosage for Metformin Hydrochloride Extended-Release Tablets:

Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew (2.1)

Starting dose: 500 mg orally once daily with the evening meal (2.1)

Increase the dose in increments of 500 mg weekly, up to a maximum of 2,000 mg once daily with the evening meal

(2.1)

Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release

tablets once daily at the same total daily dose, up to 2,000 mg once daily (2.1)

Renal Impairment:

Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3)

Do not use in patients with eGFR below 30 mL/minute/1.73 m (2.3)

Initiation is not recommended in patients with eGFR between 30 mL/minute/1.73 m and 45 mL/minute/1.73 m

(2.3)

Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m (2.3)

Discontinue if eGFR falls below 30 mL/minute/1.73 m (2.3)

Discontinuation for Iodinated Contrast Imaging Procedures:

Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated

contrast imaging procedures (2.4)

DOSAGE FORMS AND STRENGTHS

Metformin Hydrochloride Extended-Release Tablets: 500 mg and 750 mg (3)

CONTRAINDICATIONS

Severe renal impairment (eGFR below 30 mL/min/1.73 m ) (4, 5.1)

Hypersensitivity to metformin (4)

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4)

WARNINGS AND PRECAUTIONS

Lactic Acidosis: See boxed warning. (5.1)

Vitamin B Deficiency: Metformin may lower vitamin B levels. Measure hematological parameters annually and

vitamin B at 2 to 3 year intervals and manage any abnormalities. (5.2)

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used

in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be

required (5.3)

ADVERSE REACTIONS

For metformin hydrochloride extended-release tablets, the most common adverse reactions (> 5.0%) are diarrhea,

nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TAGI Pharma, Inc. at 1-855-225-8244 or FDA at 1-800-

FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7)

Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the

accumulation of metformin. Consider the benefits and risks of concomitant use (7)

Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7)

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended

pregnancy. (8.3)

Geriatric Use: Assess renal function more frequently. (8.5)

Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LACTIC ACIDOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

2.3 Recommendations for Use in Renal Impairment

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

5.2 Vitamin B

Deficiency

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

5.4 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

12

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.2 Metformin Hydrochloride Extended-Release Tablets

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS

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 mcg/mL [see Warnings and

Precautions (5.1)].

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 (2.3), Contraindications (4), Warnings

and Precautions (5.1)].

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

hydrochloride extended-release tablets and institute general supportive measures in a

hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to

improve glycemic control in adults with type 2 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

Sections or subsections omitted from the full prescribing information are not listed.

Metformin Hydrochloride Extended-Release Tablets

Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.

The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg

orally once daily with the evening meal.

Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability,

up to a maximum of 2,000 mg once daily with the evening meal.

If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2,000

mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1,000 mg twice

daily. If higher doses are required, switch to metformin hydrochloride tablets at total daily doses up

to 2,550 mg administered in divided daily doses, as described above.

Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride

extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily.

2.3 Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and

periodically thereafter.

Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated

glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m .

Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30

mL/minute/1.73 m and 45 mL/minute/1.73 m is not recommended.

In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below

45 mL/min/1.73 m , assess the benefit risk of continuing therapy.

Discontinue metformin hydrochloride extended-release tablets if the patient's eGFR later falls

below 30 mL/minute/1.73 m [see Warnings and Precautions (5.1)].

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated

contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 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 extended-release tablets if renal function is stable.

3 DOSAGE FORMS AND STRENGTHS

Metformin hydrochloride extended-release tablets, USP are available as:

Metformin hydrochloride extended-release tablets USP, 500 mg are oval white tablets, with "OE"

debossed on one side and "584" debossed on the other side.

Metformin hydrochloride extended-release tablets USP, 750 mg are white, capsule shaped tablets,

with "OE" debossed on one side and "585" debossed on the other side.

4 CONTRAINDICATIONS

Metformin hydrochloride extended-release tablets are contraindicated in patients with:

Severe renal impairment (eGFR below 30 mL/min/1.73 m ) [see Warnings and Precautions (5.1)].

Hypersensitivity to metformin.

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

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.

These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,

myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and

resistant bradyarrhythmias have occurred with severe acidosis.

Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5

mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:

pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake

of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in

patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted

promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride

extended-release tablets. In metformin hydrochloride extended-release tablets treated patients with a

diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the

acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of

up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of

symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur,

instruct them to discontinue metformin hydrochloride extended-release tablets and report these

symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis,

recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided

below:

Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily

occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the

severity of renal impairment because metformin is substantially excreted by the kidney. Clinical

recommendations based upon the patient's renal function include [see Dosage and Administration

(2.1), Clinical Pharmacology (12.3)]:

Before initiating metformin hydrochloride extended-release tablets, obtain an estimated

glomerular filtration rate (eGFR).

Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR

less than 30 mL/min/1.73 m [see Contraindications (4)].

Initiation of metformin hydrochloride extended-release tablets is not recommended in patients

with eGFR between 30 mL/min/1.73 m and 45 mL/min/1.73 m .

Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release

tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal

function should be assessed more frequently.

In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45

mL/min/1.73 m , assess the benefit and risk of continuing therapy.

Drug interactions — The concomitant use of metformin hydrochloride extended-release tablets with

specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal

function, result in significant hemodynamic change, interfere with acid-base balance, or increase

metformin accumulation. Consider more frequent monitoring of patients.

Age 65 or greater — The risk of metformin-associated lactic acidosis increases with the patient's

age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac

impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiologic studies with contrast — Administration of intravascular iodinated contrast agents in

metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic

acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an

iodinated contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 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

patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after

the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal

function is stable.

Surgery and other procedures — Withholding of food and fluids during surgical or other procedures

may increase the risk for volume depletion, hypotension, and renal impairment. Metformin

hydrochloride extended-release tablets should be temporarily discontinued while patients have

restricted food and fluid intake.

Hypoxic states — Several of the postmarketing cases of metformin-associated lactic acidosis

occurred in the setting of acute congestive heart failure (particularly when accompanied by

hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,

sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis

and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride

extended-release tablets.

Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism.

Patients should be warned against excessive alcohol intake while receiving metformin

hydrochloride extended-release tablets.

Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-

associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate

blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients

with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B

Deficiency

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels

of previously normal serum vitamin B

levels was observed in approximately 7% of patients. Such

decrease, possibly due to interference with B

absorption from the B

-intrinsic factor complex, may

be associated with anemia but appears to be rapidly reversible with discontinuation of metformin

hydrochloride tablets or vitamin B

supplementation. Certain individuals (those with inadequate vitamin

or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B

levels. Measure hematologic parameters on an annual basis and vitamin B

at 2 to 3 year intervals in

patients on metformin hydrochloride extended-release tablets and manage any abnormalities [see Adverse

Reactions (6.1)].

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin

hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with

insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may

be required to minimize the risk of hypoglycemia when used in combination with metformin

hydrochloride extended-release tablets [see Drug Interactions (7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction

with metformin hydrochloride extended-release tablets.

6 ADVERSE REACTIONS

The following adverse reactions are also discussed elsewhere in the labeling:

Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]

Vitamin B

Deficiency [see Warnings and Precautions (5.2)]

Hypoglycemia [see Warnings and Precautions (5.3)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

12

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

Metformin Hydrochloride Extended-Release Tablets

In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release

tablets. 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 1.

Table 1: Adverse Reactions from Clinical Trials of Metformin

Hydrochloride Extended-Release Tablets Occurring > 5% and More

Common than Placebo in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride

Extended-Release Tablets

(n = 781)

Placebo

(n = 195)

Diarrhea

Nausea/Vomiting

Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of

patients. 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

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

postmarketing use of metformin.

7 DRUG INTERACTIONS

Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release

tablets.

Table 2: Clinically Significant Drug Interactions with Metformin

Hydrochloride Extended-Release Tablets

Carbonic Anhydrase Inhibitors

Clinical Impact:

Carbonic anhydrase inhibitors frequently cause a

decrease in serum bicarbonate and induce non-anion gap,

hyperchloremic metabolic acidosis. Concomitant use of

these drugs with metformin hydrochloride extended-

release tablets may increase the risk for lactic acidosis.

Intervention:Consider more frequent monitoring of these patients.

Examples:

Topiramate, zonisamide, acetazolamide or

dichlorphenamide.

Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets

Clearance

Concomitant use of drugs that interfere with common

Clinical Impact:

renal tubular transport systems involved in the renal

elimination of metformin (e.g., organic cationic

transporter-2 [OCT2] / multidrug and toxin extrusion

[MATE] inhibitors) could increase systemic exposure to

metformin and may increase the risk for lactic acidosis

[see Clinical Pharmacology (12.3)].

Intervention:

Consider the benefits and risks of concomitant use with

metformin hydrochloride extended-release tablets.

Examples:Ranolazine, vandetanib, dolutegravir, and cimetidine.

Alcohol

Clinical Impact:

Alcohol is known to potentiate the effect of metformin on

lactate metabolism.

Intervention:

Warn patients against excessive alcohol intake while

receiving metformin hydrochloride extended-release

tablets.

Insulin Secretagogues or Insulin

Clinical Impact:

Coadministration of metformin hydrochloride extended-

release tablets with an insulin secretagogue (e.g.,

sulfonylurea) or insulin may increase the risk of

hypoglycemia.

Intervention:

Patients receiving an insulin secretagogue or insulin may

require lower doses of the insulin secretagogue or

insulin.

Drugs Affecting Glycemic Control

Clinical Impact:

Certain drugs tend to produce hyperglycemia and may

lead to loss of glycemic control.

Intervention:

When such drugs are administered to a patient receiving

metformin hydrochloride extended-release tablets,

observe the patient closely for loss of blood glucose

control. When such drugs are withdrawn from a patient

receiving metformin hydrochloride extended-release

tablets, observe the patient closely for hypoglycemia.

Examples:

Thiazides and other diuretics, corticosteroids,

phenothiazines, thyroid products, estrogens, oral

contraceptives, phenytoin, nicotinic acid,

sympathomimetics, calcium channel blockers, and

isoniazid.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited data with metformin hydrochloride extended-release tablets in pregnant women are not

sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies

with metformin use during pregnancy have not reported a clear association with metformin and major

birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with

poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].

No adverse developmental effects were observed when metformin was administered to pregnant

Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5 times,

respectively, a 2,550 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational

diabetes mellitus with an HbA

> 7 and has been reported to be as high as 20% to 25% in women with

a HbA

> 10. The estimated background risk of miscarriage for the indicated population is unknown. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis,

pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly

controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia

related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and

major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used

during pregnancy. However, these studies cannot definitely establish the absence of any metformin-

associated risk because of methodological limitations, including small sample size and inconsistent

comparator groups.

Animal Data

Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant

rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a

2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively.

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

8.2 Lactation

Risk Summary

Limited published studies report that metformin is present in human milk [see Data]. However, there is

insufficient information to determine the effects of metformin on the breastfed infant and no available

information on the effects of metformin on milk production. Therefore, the developmental and health

benefits of breastfeeding should be considered along with the mother's clinical need for metformin

hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from

metformin hydrochloride extended-release tablets or from the underlying maternal condition.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in

infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio

ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of

use of metformin during lactation because of small sample size and limited adverse event data collected

in infants.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin

hydrochloride extended-release tablets may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Metformin Hydrochloride Extended-Release Tablets

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

not been established.

8.5 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. 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 and Precautions (5.1)].

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic

acidosis increases with the degree of renal impairment. Metformin hydrochloride extended-release

tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration

rate (eGFR) below 30 mL/min/1.73 m [see Dosage and Administration (2.3), Contraindications (4),

Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic

acidosis. Metformin hydrochloride extended-release tablets are not recommended in patients with

hepatic impairment. [see Warnings and Precautions (5.1)].

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

overdose cases [see Warnings and Precautions (5.1)]. 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.

11 DESCRIPTION

Metformin hydrochloride extended-release tablets, USP contain the antihyperglycemic agent metformin,

which is a biguanide, in the form of monohydrochloride. The chemical name of metformin

hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as

shown below:

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of

C H N · HCl and a molecular weight of 165.63. It is freely soluble in water and is practically

insoluble in acetone, ether, and chloroform. The pKa 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, which is equivalent to 389.93 mg, 584.90 mg metformin base, respectively.

Metformin hydrochloride extended-release tablets USP, 500 mg and 750 mg contain the inactive

ingredients carboxymethylcellulose sodium, copovidone, hypromellose, magnesium stearate and

microcrystalline cellulose.

The USP dissolution test is pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic

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

increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains

unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.3 Pharmacokinetics

Absorption

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. Peak plasma levels are approximately 20%

lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption

(as measured by AUC) is comparable to metformin hydrochloride tablets.

At steady state, the AUC and C

are less than dose proportional for metformin hydrochloride

extended-release tablets within the range of 500 to 2,000 mg administered once daily. Peak plasma

levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1,000, 1,500, and 2,000 mg once-daily

doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin

hydrochloride extended-release tablets at a 2,000 mg once-daily dose is similar to the same total daily

dose administered as metformin hydrochloride tablets 1,000 mg twice daily. After repeated

administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in

plasma.

Effect of food: Food decreases the extent of absorption 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 versus 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

hydrochloride with food, compared to the same tablet strength administered fasting.

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.

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.

Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism

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.

Elimination

Renal clearance (see Table 3) is approximately 3.5 times greater than creatinine clearance, which

indicates that tubular secretion is the major route of metformin elimination. Following oral

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

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

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

distribution.

Specific Populations

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 2) [See Dosage and Administration (2.3), Contraindications

(4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [See

Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

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. It appears that the change in

metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see

Table 3). [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Table 3: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters

Following Single or Multiple Oral Doses of Metformin Hydrochloride

Tablets

Subject Groups: Metformin

Hydrochloride Tablets

Dose (number of subjects)

C

(mcg/mL)

T

(hrs)

Renal

Clearance

(mL/min)

Healthy, nondiabetic adults:

500 mg single dose (24)

1.03 (± 0.33)

2.75 (± 0.81)

600 (± 132)

850 mg single dose (74)

1.60 (± 0.38)

2.64 (± 0.82)

552 (± 139)

850 mg three times daily for

19 doses (9)

2.01 (± 0.42)

1.79 (± 0.94)

642 (± 173)

Adults with type 2 diabetes

mellitus :

850 mg single dose (23)

1.48 (± 0.5)

3.32 (± 1.08)

491 (± 138)

850 mg three times daily for

19 doses (9)

1.90 (± 0.62)

2.01 (± 1.22)

550 (± 160)

Elderly , 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)

1.86 (± 0.52)

3.20 (± 0.45)

384 (± 122)

Moderate (CL 31 to 60

mL/min) (4)

4.12 (± 1.83)

3.75 (± 0.50)

108 (± 57)

Severe (CL 10 to 30

3.93 (± 0.92)

4.01 (± 1.10)

130 (± 90)

*

max

max

#

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 mellitus when analyzed according to gender (males = 19, females = 16).

Race

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

Drug Interactions

In Vivo Assessment of Drug Interactions

Table 4: Effect of Coadministered Drug on Plasma Metformin Systemic

Expos ure

Coadminis tered

Drug

Dose of

Coadminis tered

Drug

Dose of

Metformin

Geometric Mean Ratio

(ratio with/without

coadministered drug)

No Effect = 1.00

AUC

C

No dosing adjustments required for the following:

Glyburide

5 mg

850 mg

metformin

0.91

0.93

Furosemide

40 mg

850 mg

metformin

1.09

1.22

Nifedipine

10 mg

850 mg

metformin

1.16

1.21

Propranolol

40 mg

850 mg

metformin

0.90

0.94

Ibuprofen

400 mg

850 mg

metformin

1.05

1.07

Cationic drugs eliminated by renal tubular secretion may reduce

metformin elimination [See Warnings and Precautions (5.1) and Drug

Interactions (7).]

Cimetidine

400 mg

850 mg

metformin

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis [See

Warnings and Precautions (5.1) and Drug Interactions (7).]

Topiramate

100 mg

500 mg

metformin

1.25

1.17

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)

CLcr = creatinine clearance normalized to body surface area of 1.73 m

*

*

max

All metformin and coadministered drugs were given as single doses

AUC = AUC (INF)

Ratio of arithmetic means

At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every

Table 5: Effect of Metformin on Coadministered Drug Systemic

Expos ure

Coadminis tered

Drug

Dose of

Coadminis tered

Drug

Dose of

Metformin

Geometric Mean Ratio

(ratio with/without

metformin)

No Effect = 1.00

AUC

C

No dosing adjustments required for the following:

Glyburide

5 mg

850 mg

glyburide

0.78

0.63

Furosemide

40 mg

850 mg

furosemide

0.87

0.69

Nifedipine

10 mg

850 mg

nifedipine

1.10

1.08

Propranolol

40 mg

850 mg

propranolol

1.01

1.02

Ibuprofen

400 mg

850 mg

ibuprofen

0.97

1.01

Cimetidine

400 mg

850 mg

cimetidine

0.95

1.01

13 NONCLINICAL TOXICOLOGY

13.1 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 1,500 mg/kg/day,

respectively. These doses are both approximately 3 times the maximum recommended human daily dose

of 2,550 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 2 times the maximum recommended human daily dose of 2,550 mg

based on body surface area comparisons.

14 CLINICAL STUDIES

14.2 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 mellitus

who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a

mean baseline HbA of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was

increased to 1,500 mg once daily if at Week 12 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%

12 hours; AUC = AUC

0-12 h

*

*

max

All metformin and coadministered drugs were given as single doses

AUC = AUC (INF) unless otherwise noted

Ratio of arithmetic means, p-value of difference < 0.05

AUC (0-24 hr) reported

Ratio of arithmetic means

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 mellitus who had failed to achieve glycemic control with diet

and exercise. The results are shown in Table 6.

Table 6: Mean Changes from Baseline in HbA and Fasting Plasma Glucose at

Week 16 Comparing Metformin Hydrochloride Extended-Release Tablets vs

Placebo in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride Extended-Release Tablets

Placebo

500 mg

Once

Daily

1,000 mg

Once

Daily

1,500 mg

Once

Daily

2,000 mg

Once

Daily

1,000 mg

Twice

Daily

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

Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the metformin

hydrochloride extended-release tablets 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg once daily, 1,000

mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16

was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively.

A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken

once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast

and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with

metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The

results are shown in Table 7.

Table 7: Mean Changes from Baseline in HbA and Fasting Plasma Glucose at

Week 24 Comparing Metformin Hydrochloride Extended-Release Tablets vs

Metformin Hydrochloride Tablets in Patients with Type 2 Diabetes Mellitus

Metformin

Hydrochloride

Tablets 500 mg

Twice Daily

Metformin Hydrochloride Extended-

Release Tablets

1,000 mg

Once Daily

1,500 mg

Once Daily

Hemoglobin A

(%)

(n = 67)

(n = 72)

(n = 66)

Baseline

7.06

6.99

7.02

Change at FINAL

VISIT

0.14

0.27

0.13

1c

All comparisons versus Placebo

1c

1c

1c

VISIT

(95% CI)

(–0.04, 0.31)

(0.11, 0.43)

(–0.02, 0.28)

FPG (mg/dL)

(n = 69)

(n = 72)

(n = 70)

Baseline

127.2

131.0

131.4

Change at FINAL

VISIT

14.0

11.5

(95% CI)

(7.0, 21.0)

(4.4, 18.6)

(1.0, 14.2)

Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500

mg twice daily, and metformin hydrochloride extended-release tablets 1,000 mg and 1,500 mg once

daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and

0.9 lbs, respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 63629-8166

NDC: 63629-8166-1 180 TABLET, EXTENDED RELEASE in a BOTTLE

NDC: 63629-8166-2 30 TABLET, EXTENDED RELEASE in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Lactic Acidosis:

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development.

Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to

promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual

somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake

and inform patients about importance of regular testing of renal function while receiving metformin

hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking

metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as

temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Hypoglycemia

Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets

are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant

therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its

development [see Warnings and Precautions (5.3)].

Vitamin B

Deficiency:

Inform patients about importance of regular hematological parameters while receiving metformin

hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Females of Reproductive Age:

Inform females that treatment with metformin hydrochloride extended-release tablets may result in

ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use

in Specific Populations (8.3)].

Metformin Hydrochloride Extended-Release Tablets Administration Information:

Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not

crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as

n = 68

12

a soft mass that may resemble the original tablet.

Manufactured by:

CSPC Ouyi Pharmaceutical Co., Ltd.

Shijiazhuang, Hebei, China, 052160

Manufactured for:

TAGI Pharma, Inc.

South Beloit, IL 61080

PATIENT INFORMATION

Metformin Hydrochloride Extended-Release Tablets, USP

(met for' min hye'' droe klor' ide)

Read the Patient Information that comes with metformin hydrochloride extended-release tablets before

you start taking it and each time you get a refill. There may be new information. This leaflet does not

take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about metformin hydrochloride extended-

release tablets?

Serious side effects can happen in people taking metformin hydrochloride extended-release

tablets, including:

Lactic Acidosis. Metformin hydrochloride, the medicine in metformin hydrochloride extended-release

tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the

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

Stop taking metformin hydrochloride extended-release tablets and call your healthcare provider

right away if you get any of the following symptoms of lactic acidosis:

feel very weak and tired

have unusual (not normal) muscle pain

have trouble breathing

have unusual sleepiness or sleep longer than usual

have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea

feel cold, especially in your arms and legs

feel dizzy or lightheaded

have a slow or irregular heartbeat

You have a higher chance of getting lactic acidosis if you:

have kidney problems. People whose kidneys are not working properly should not take metformin

hydrochloride extended-release tablets.

have liver problems.

have congestive heart failure that requires treatment with medicines.

drink a lot of alcohol (very often or 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 certain x-ray tests with injectable dyes or contrast agents.

have surgery.

have a heart attack, severe infection, or stroke.

are 80 years of age or older and have not had your kidney function tested.

What are metformin hydrochloride extended-release tablets?

Metformin hydrochloride extended-release tablets are prescription medicines that contain metformin

hydrochloride. Metformin hydrochloride extended-release tablets are used with diet and exercise to

help control high blood sugar (hyperglycemia) in adults with type 2 diabetes.

Metformin hydrochloride extended-release tablets are not for people with type 1 diabetes.

Metformin hydrochloride extended-release tablets are not for people with diabetic ketoacidosis

(increased ketones in your blood or urine).

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 extended-release

tablets do not cause your body to make more insulin.

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

are allergic to the metformin hydrochloride in metformin hydrochloride extended-release tablets or

any of the ingredients in metformin hydrochloride extended-release tablets. See the end of this

leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets.

are going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to

have surgery and not able to eat or drink much. In these situations, metformin hydrochloride

extended-release tablets will need to be stopped for a short time. Talk to your healthcare provider

about when you should stop metformin hydrochloride extended-release tablets and when you should

start metformin hydrochloride extended-release tablets again. See "What is the most important

information I should know about metformin hydrochloride extended-release tablets?"

What should I tell my healthcare provider before taking metformin hydrochloride extended-

release tablets?

Before taking metformin hydrochloride extended-release tablets, tell your healthcare provider if you:

have type 1 diabetes. Metformin hydrochloride extended-release tablets should not be used to treat

people with type 1 diabetes.

have a history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in

the blood or urine). Metformin hydrochloride extended-release tablets should not be used for the

treatment of diabetic ketoacidosis.

have kidney problems.

have liver problems.

have heart problems, including congestive heart failure.

are older than 80 years. If you are over 80 years old you should not take metformin hydrochloride

extended-release tablets unless your kidneys have been checked and they are normal.

drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking.

are taking insulin.

have any other medical conditions.

are pregnant or plan to become pregnant. It is not known if metformin hydrochloride will harm your

unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control

your blood sugar while you are pregnant.

are breast-feeding or plan to breast-feed. It is not known if metformin hydrochloride passes into

your breast milk. Talk with your healthcare provider about the best way to feed your baby while you

take metformin hydrochloride extended-release tablets.

Tell your healthcare provider about all the medicines you take, including prescription and

nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list

of them to show your healthcare provider and pharmacist when you get a new medicine.

Metformin hydrochloride extended-release tablets may affect the way other medicines work, and

other medicines may affect how metformin hydrochloride extended-release tablets work.

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

Metformin hydrochloride extended-release tablets have not been studied in children.

How should I take metformin hydrochloride extended-release tablets?

Take metformin hydrochloride extended-release tablets exactly as your healthcare provider tells

you.

Metformin hydrochloride extended-release tablets should be taken with meals to help lessen an

upset stomach side effect.

Swallow metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew

metformin hydrochloride extended-release tablets.

You may sometimes pass a soft mass in your stools (bowel movement) that looks like metformin

hydrochloride extended-release tablets. This is not harmful and will not affect the way metformin

hydrochloride extended-release tablets work to control your diabetes.

When your body is under some types of stress, such as fever, trauma (such as a car accident),

infection, or surgery, the amount of diabetes medicine that you need may change. Tell your

healthcare provider right away if you have any of these problems.

Your healthcare provider should do blood tests to check how well your kidneys are working before

and during your treatment with metformin hydrochloride extended-release tablets.

Your healthcare provider will check your diabetes with regular blood tests, including your blood

sugar levels and your hemoglobin A

Follow your healthcare provider's instructions for treating blood sugar that is too low

(hypoglycemia). Talk to your healthcare provider if low blood sugar is a problem for you. See

"What are the possible side effects of metformin hydrochloride extended-release tablets?"

Check your blood sugar as your healthcare provider tells you to.

Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended-

release tablets.

If you miss a dose of metformin hydrochloride extended-release tablets, take your next dose as

prescribed unless your healthcare provider tells you differently. Do not take an extra dose the next

day.

If you take too much metformin hydrochloride extended-release tablets, call your healthcare

provider, local Poison Control Center, or go to the nearest hospital emergency room right away.

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. Metformin, the active ingredient in metformin hydrochloride extended-release

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

hos pital.

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 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 extended-release 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

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.

How should I store metformin hydrochloride extended-release tablets?

Store metformin hydrochloride extended-release tablets at 68°F to 77°F (20°C to 25°C).

Keep metformin hydrochloride extended-release tablets and all medicines out of the reach of

children.

General information about the use of metformin hydrochloride extended-release tablets

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.

What are the ingredients of metformin hydrochloride extended-release tablets?

Active ingredients of metformin hydrochloride extended-release tablets: metformin hydrochloride.

Inactive ingredients in each tablet of metformin hydrochloride extended-release tablets 500 mg and 750

mg: carboxymethylcellulose sodium, copovidone, hypromellose, magnesium stearate and

microcrystalline cellulose.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that

your body produces does not work as well as it should. Your body can also make too much sugar. When

this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.

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, and by certain medicines when necessary.

Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar

(hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.

Manufactured by:

CSPC Ouyi Pharmaceutical Co., Ltd.

Shijiazhuang, Hebei, China, 052160

Manufactured for:

TAGI Pharma, Inc.

South Beloit, IL 61080

Rev. 09/2018

METFORMIN HCL ER 500 TABLET

METFORMIN HYDROCHLORIDE

metformin hydrochloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 16 6 (NDC:51224-0 0 7)

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

Bryant Ranch Prepack

Ingredient Name

Stre ng th

Co po vido ne K2 5-3 1 (UNII: D9 C330 MD8 B)

ca rbo xymethylcellulo se so dium, unspecified fo rm (UNII: K6 79 OBS311)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

OE;58 4

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 16 6 -1

18 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/29 /20 19

2

NDC:6 36 29 -8 16 6 -2

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

0 7/29 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 321

0 4/17/20 0 8

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 16 6 ) , RELABEL(6 36 29 -8 16 6 )

Revised: 8/2019

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