METFORMIN HYDROCHLORIDE - metformin hydrochloride tablet, film coated, 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:
NorthStar RxLLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Metformin hydrochloride extended-release tablets, USP 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/minute/1.73 m2 ) [see Warnings and Precautions (5.1)] . ·   Known 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 w
Product summary:
Metformin hydrochloride extended-release tablets, USP - 500 mg are available as white to off-white, circular, biconvex, film-coated tablets imprinted with "305" in black ink on one side and plain on the other side. Metformin hydrochloride extended-release tablets, USP  - 1000 mg are available as white to off-white, circular, biconvex, film-coated tablets imprinted with "306" in black ink on one side and plain on the other side. They are supplied as follows: 500 mg tablets: Bottles of 100’s with Child Resistant Cap…..................NDC 16714-938-01 1000 mg tablets: Bottles of 90’s with Child Resistant Cap…....................NDC 16714-939-01 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
16714-938-01, 16714-939-01

METFORMIN HYDROCHLORIDE - metformin hydrochloride tablet, film coated, extended

release

NorthStar RxLLC

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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 metformin-associated 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 is 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

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

Increase the dose in increments of 500 mg every 1 to 2 weeks, up to a maximum of 2,000 mg once daily with the

evening meal. (2.1)

Patients receiving metformin hydrochloride (HCl) 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)

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

Renal Impairment:

Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (2.2)

Do not use in patients with eGFR below 30 mL/minute/1.73 m .

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

Assess risk/benefit of continuing metformin hydrochloride extended-release tablets if eGFR falls below 45

mL/minute/1.73 m .

Discontinue if eGFR falls below 30 mL/minute/1.73 m .

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. (2.3)

DOSAGE FORMS AND STRENGTHS

Metformin Hydrochloride Extended-Release Tablets: 500 mg and 1,000 mg (3)

CONTRAINDICATIONS

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

Known 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 B12 levels. Monitor hematological parameters annually and

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

12

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

Adverse reactions occurring >5% in metformin hydrochloride extended-release tablets clinical trials: hypoglycemia,

diarrhea, and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 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.

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: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LACTIC ACIDOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage and Administration

2.2 Recommendations for Use in Renal Impairment

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

5.2 Vitamin B12 Deficiency

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

5.4 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Trials 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

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

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 in the full prescribing information [see Dosage and Administration

(2.2), Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].

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, USP 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 and Administration

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

orally once daily with the evening meal.

Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and

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

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

Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride

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

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

If a dose of metformin hydrochloride extended-release tablets is missed, instruct patients not to take

two doses the same day and to resume their usual dose of metformin hydrochloride extended-

release tablets with the next schedule dose.

2.2 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 to 45 mL/minute/1.73 m is not recommended.

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

45 mL/minute/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 Contraindications (4) and Warnings and Precautions (5.1)].

2.3 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 and 60 mL/minute/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 [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS AND STRENGTHS

Metformin hydrochloride extended-release tablets, USP 500 mg are available as white to off-white,

circular, biconvex, film-coated tablets imprinted with “305” in black ink on one side and plain on the

other side.

Metformin hydrochloride extended-release tablets, USP 1000 mg are available as white to off-white,

circular, biconvex, film-coated tablets imprinted with “306” in black ink on one side and plain on the

other side.

4 CONTRAINDICATIONS

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

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

· Known 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, hypothermia,

hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated

lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), 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 HCl is dialyzable, with a clearance of up to 170

mL/minute 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 (2.2) and 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/minute/1.73 m [see Contraindications (4)].

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

with eGFR between 30 to 45 mL/minute/1.73 m .

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

tablets. In patients at increased 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 later 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 [see Drug Interactions (7)]. Therefore, 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 [see Use in Specific

Populations (8.5)].

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in

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

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

iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 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 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 also cause

prerenal azotemia. When such events occur, discontinue metformin hydrochloride extended-release

tablets.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism, and this

may increase the risk of metformin-associated lactic acidosis. Warn patients 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 B12 Deficiency

In clinical trials of 29-week duration with metformin HCl tablets, 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 or

vitamin B

supplementation. Certain individuals (those with inadequate vitamin B

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 discussed in more detail in other sections of 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 Trials Experience

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

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.

In clinical trials conducted in the U.S., over 1,000 patients with type 2 diabetes mellitus have been

treated with metformin hydrochloride extended-release tablets 1,500 to 2,000 mg/day in active-

controlled and placebo-controlled studies with the 500 mg dosage form. In the add-on to sulfonylurea

study, patients receiving background glyburide therapy were randomized to receive add-on treatment of

either one of three different regimens of metformin hydrochloride extended-release tablets or placebo.

In total, 431 patients received metformin hydrochloride extended-release tablets and glyburide and 144

patients received placebo and glyburide. Adverse reactions reported in greater than 5% of patients

treated with metformin hydrochloride extended-release tablets that were more common in the combined

metformin hydrochloride extended-release tablets and glyburide group than in the placebo and

glyburide group are shown in Table 1. In 0.7% of patients treated with metformin hydrochloride

extended-release tablets and glyburide, diarrhea was responsible for discontinuation of study

medication compared to no patients in the placebo and glyburide group.

Table 1: Adverse Reactions Reported by >5%* of Patients for the Combined Metformin

Hydrochloride Extended-Release Tablets Groups Versus Placebo Group

Adverse Reaction

Metformin Hydrochloride

Extended-Release Tablets

+ Glyburide

(n = 431)

Placebo + Glyburide

(n = 144)

Hypoglycemia

Diarrhea

Nausea

Adverse reactions that were more common in the metformin hydrochloride extended-release tablets-

treated than in the placebo-treated patients.

Laboratory Tests

Vitamin B

Concentrations

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

previously normal serum vitamin B

levels was observed in approximately 7% of patients.

6.2 Postmarketing Experience

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

hydrochloride extended-release tablets. 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.

12

Intervention:

Consider more frequent monitoring of these patients.

Examples:

Topiramate, zonisamide, acetazolamide or dichlorphenamide.

Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance

Clinical Impact:

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) could increase systemic exposure to

metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)].

Intervention:

Consider

the benefits

risks

concomitant

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

patient

receiving

metformin

hydrochloride

extended-release tablets, observe the patient closely for loss of blood glucose control.

When

such

drugs

are withdrawn

from

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 3 and 1 times,

respectively, a 2,000 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 pregestational diabetes

mellitus with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with an HbA1c

>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 HCl was not teratogenic or embyrolethal when administered to rats prior to pregnancy

through the period of organogenesis at doses up to 900 mg/kg, or when administered to rabbits during

the period of organogenesis at doses up to 90 mg/kg.

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

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

not been established.

8.5 Geriatric Use

Clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers

of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 Dosage and Administration (2.2) and 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

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 (2.2), 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 HCl 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/minute 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 contain the biguanide antihyperglycemic agent

metformin in the form of monohydrochloride salt. The chemical name of metformin hydrochloride is

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

Metformin hydrochloride is a white crystalline compound with a molecular formula of C H N 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 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

are modified release dosage forms that contain 500 mg or 1000 mg of metformin HCl, USP. Each tablet

contains anhydrous citric acid,colloidal silicon dioxide, dibutyl sebacate,ethylcellulose, magnesium

stearate, povidone, sodium bicarbonate and sodium lauryl sulfate. The imprinting ink contains ammonium

hydroxide, iron oxide black, N-butyl alcohol, propylene glycol and shellac glaze.

USP dissolution test is pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, 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 1,000 mg (2x500 mg tablets) metformin hydrochloride extended-

release tabletsafter a meal, the time to reach maximum plasma metformin concentration (T

) is

achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects,

once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by

area under the curve (AUC), and up to 35% higher C

, of metformin relative to the immediate-release

given as 500 mg twice daily. At usual clinical doses and dosing schedules of metformin, steady state

plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL.

In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be

similar to two 500 mg tablets under fed conditions based on equivalent C

and AUCs for the two

formulations.

Single oral doses of metformin hydrochloride extended-release tablets from 500 mg to 2,500 mg

resulted in less than proportional increase in both AUC and C

Effect of food: Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from

metformin hydrochloride extended-release tablets by about 38% and 73%, respectively, relative to

fasting. Both meals prolonged metformin T

by approximately 3 hours but C

was not affected.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg

metformin HCl 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 healthy 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.

Excretion

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular

secretion is the major route of metformin elimination. Following oral administration, approximately

90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma

elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately

17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Impairment

Following a single-dose administration of metformin hydrochloride extended-release tablets 500 mg in

subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were

decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was

27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36-fold

greater in subjects with moderate renal impairment as compared to healthy subjects. [see Dosage and

Administration (2.2), Contraindications (4), and Warnings and Precautions (5.1).]

Hepatic Impairment

No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted

in subjects 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 HCl in healthy elderly subjects

suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by

64% and C

is increased by 76%, 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 Dosage and Administration (2) and Warnings and Precautions (5.1).]

Gender

In the pharmacokinetic studies in healthy volunteers, there were no important differences between male

and female subjects with respect to metformin AUC and t

. However, C

for metformin was 40%

higher in female subjects as compared to males. In controlled clinical studies in patients with type 2

diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females.

The gender differences for C

are unlikely to be clinically important.

Race

A trend towards 10% higher metformin C

and AUC values for metformin are obtained in Asian

subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian

and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin

HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249),

blacks (n=51) and Hispanics (n=24).

Pediatrics

There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in

pediatric patients.

Drug Interactions

Specific pharmacokinetic drug interaction studies with metformin hydrochloride extended-release

tablets have not been performed except for one with glyburide. However, such studies have been

performed on metformin HCl tablets.

Table 3: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadminis tered

Drug

Dose of

Coadminis tered

Drug

Dose of

Metformin

HCl

Geometric Mean Ratio

(ratio with/without coadministered drug)

No Effect = 1

AUC

C

No dosing adjustments required for the following:

Glyburide

5 mg

500 mg

0.98

0.99

Furosemide

40 mg

850 mg

1.09

1.22

Nifedipine

10 mg

850 mg

1.16

1.21

Propranolol

40 mg

850 mg

0.94

Ibuprofen

400 mg

850 mg

1.05

1.07

Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of

metformin: [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Cimetidine

400 mg

850 mg

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis:

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

Topiramate

100 mg

500 mg

1.25

1.17

All metformin HCl and coadministered drugs were given as single doses.

AUC = AUC

Ratio of arithmetic means

Metformin hydrochloride extended-release tablets 500 mg

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

Table 4: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadminis tered

Drug

Dose of

Coadminis tered

Drug

Dose of

Metformin

HCl

Geometric Mean Ratio

(ratio with/without coadministered drug)

No effect = 1

AUC

C

No dosing adjustments required for the following:

Glyburide

5 mg

500 mg

0.78

0.63

Furosemide

40 mg

850 mg

0.87

0.69

Nifedipine

10 mg

850 mg

1.08

1

1

2

max

0–inf

0-12h

1

1

2

max

Propranolol

40 mg

850 mg

1.01

0.94

Ibuprofen

400 mg

850 mg

0.97

1.01

Cimetidine

400 mg

850 mg

0.95

1.01

All metformin HCl and coadministered drugs were given as single doses.

AUC = AUC

unless otherwise noted

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

hr reported

Ratio of arithmetic means

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300,

and 450 mg/kg/day in males and 150, 450, 900, and 1,200 mg/kg/day in females. These doses are

approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum

recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of

carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was

also performed in Tg.AC transgenic mice at doses up to 2,000 mg applied dermally. No evidence of

carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal

aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of

male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day,

which is approximately 3 times the maximum recommended human daily dose based on body surface

area comparisons.

14 CLINICAL STUDIES

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study

conducted in patients type 2 diabetes mellitus, metformin hydrochloride extended-release tablets1,500

mg once daily, metformin hydrochloride extended-release tablets 1,500 per day in divided doses (500

mg in the morning and 1,000 mg in the evening), and metformin hydrochloride extended-release

tablets 2,000 mg once daily were compared to immediate-release metformin HCl tablets 1,500 mg per

day in divided doses (500 mg in the morning and 1,000 mg in the evening). This study included patients

(n=338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients

treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors,

thiazolidinediones, or meglitinides), and patients (n=368) receiving metformin HCl tablets up to 1,500

mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who

were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout.

Patients randomized to metformin hydrochloride extended-release tablets began titration from 1,000

mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release

metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1,000 mg

with dinner for the second week. The 3-week treatment period was followed by an additional 21-week

period at the randomized dose. The results are presented in Table 4.

Table 5: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24

Comparing Metformin Hydrochloride Extended-Release Tablets versus Metformin HCl Tablets*

in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride Extended-

Release Tablets

Metformin HCl

Tablets* 1,500

mg in Divided

Doses (n=174)

1,500 mg

Once Daily

(n = 178)

1,500 mg in

Divided

doses

(n = 182)

2,000 mg

Once Daily

(n = 172)

HbA1c (%), N

0–inf

0-24

Baseline

Mean Change at Final Visit

-0.7

-0.7

-1.1

-0.7

Mean

Difference from

Metformin

Tablets* (98.4% CI)

0 (-0.3, 0.3)

0 (-0.3, 0.3)

-0.4 (-0,7, -

0.1)

Fasting Plasma Glucose (mg/dL), N

Baseline

192.3

Mean Change at Final Visit

Mean

Difference from

Metformin

Tablets* (95% CI)

-6 (-15, 2)

0 (-8, 9)

-10 (-19, -1)

*Immediate-release metformin HCl tablets

Mean baseline body weight was 88.2 kg, 90.5 kg, 87.7 kg and 88.7 kg in the metformin hydrochloride

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

mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and

metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from

baseline to week 24 was -0.9 kg, -0.7 kg, -1.1 kg, and -0.9 kg in the metformin hydrochloride extended-

release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in

divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin

HCl tablets 1,500 mg in divided doses arms, respectively.

A double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study enrolled patients

with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n=144), or

who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors,

thiazolidinediones, or meglitinides, or treated with combination therapy consisting of metformin

HCl/glyburide at doses up to 1,000 mg metformin + 10 mg glyburide per day (or equivalent doses of

glipizide or glimepiride up to half the maximum therapeutic dose) (n=431). All patients were stabilized

on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide

(glyburide alone); metformin hydrochloride extended-release tablets 1,500 mg once a day + glyburide,

metformin hydrochloride extended-release tablets 2,000 mg once a day + glyburide, or metformin

hydrochloride extended-release tablets 1,000 mg twice a day + glyburide. A 3-week metformin

hydrochloride extended-release tablets titration period was followed by a 21-week maintenance

treatment period. Use of insulin and oral hypoglycemic agents other than the study drugs were

prohibited. The results are presented in Table 5.

Table 6: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 for the

Metformin Hydrochloride Extended-Release Tablets + Glyburide Groups and Placebo+

Glyburide Treatment Group in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride Extended-

Release Tablets + Glyburide*

Placebo/

Glyburide*

(n = 144)

1,500 mg

Once Daily

(n=144)

1,000 mg

Twice Daily

(n=141)

2,000 mg

Once Daily

(n=146)

HbA1c (%), N

Baseline

Mean Change at Final Visit

-0.7

-0.8

-0.7

-0.1

Mean

Difference

from

Glyburide Alone

(95% CI)

-0.8

(-1.0, -0.6)

-0.9

(-1.1, -0.7)

-0.8

(-1.0, -0.6)

Fasting Plasma Glucose (mg/dL), N

Baseline

Mean Change at Final Visit

Mean

Difference from

Glyburide Alone

(95% CI)

-29.2

(-39, -20)

-31.2

(-41, -22)

-24.9

(-35, -15)

* Glyburide was administered as 10 mg at breakfast and 5 mg at dinner.

p-value for pairwise comparison <0.001

Mean baseline body weight was 89.4 kg, 103.7 kg, 102.9 kg and 95.6 kg in the metformin hydrochloride

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

mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and

metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from

baseline to week 24 was 0.3 kg, 0.1 kg, 0 kg, and 0.7 kg in the metformin hydrochloride extended-

release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in

divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin

HCl tablets 1,500 mg in divided doses arms, respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING

Metformin hydrochloride extended-release tablets, USP - 500 mg are available as white to off-white,

circular, biconvex, film-coated tablets imprinted with "305" in black ink on one side and plain on the

other side.

Metformin hydrochloride extended-release tablets, USP - 1000 mg are available as white to off-white,

circular, biconvex, film-coated tablets imprinted with "306" in black ink on one side and plain on the

other side.

They are supplied as follows:

500 mg tablets:

Bottles of 100’s with Child Resistant Cap…..................NDC 16714-938-01

1000 mg tablets:

Bottles of 90’s with Child Resistant Cap…....................NDC 16714-939-01

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see

USP Controlled Room Temperature].

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 B12 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)].

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

a soft mass that may resemble the original tablet.

PATIENT INFORMATION

Metformin Hydrochloride

(met-FOR-min HYE-droe-KLOR-ide)

Extended-Release Tablets USP, for oral use

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

release tablets?

Metformin hydrochloride extended-release tablets can cause serious side effects, 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 buildup of lactic

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

treated in the hospital.

Stop taking metformin hydrochloride extended-release tablets and call your doctor right away if

you get any of the following symptoms of lactic acidosis:

feel very weak and tired

have unusual sleepiness or sleep longer than usual

have unusual (not normal) muscle pain

feel cold, especially in your arms and legs

have trouble breathing

feel dizzy or lightheaded

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

have a slow or irregular heartbeat

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

have severe kidney problems. See “Do not take metformin hydrochloride extended-release

tablets if you”

have liver problems.

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 or other procedure for which you need to restrict the amount of food and liquid you

eat and drink.

have congestive heart failure.

have a heart attack, severe infection, or stroke.

are 65 years of age or older.

Tell your doctor if you have any of the problems in the list above.

Tell your doctor that you are taking metformin hydrochloride extended-release tablets before you have

surgery or x-ray tests. Your doctor may need to stop metformin hydrochloride extended-release tablets

for a while if you have surgery or certain x-ray tests.

Metformin hydrochloride extended-release tablets can have other serious side effects. See “What are

the possible side effects of metformin hydrochloride extended-release tablets?”.

What are metformin hydrochloride extended-release tablets?

Metformin hydrochloride extended-release tablets are a prescription medicine that contains

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.

It is not known if metformin hydrochloride extended-release tablets are safe and effective in children.

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

have severe kidney problems.

are allergic to metformin hydrochloride or any of the ingredients in metformin hydrochloride

extended-release tablets. See the end of this Patient Information leaflet for a complete list of

ingredients in metformin hydrochloride extended-release tablets.

have a condition called metabolic acidosis, including diabetic ketoacidosis (high levels of certain

acids called “ketones” in your blood or urine).

Before taking metformin hydrochloride extended-release tablets tell your doctor about all of your

medical conditions, including if you:

have a history or risk for diabetic ketoacidosis. See “Do not take metformin hydrochloride

extended-release tablets if you:”.

have kidney problems.

have liver problems.

have heart problems, including congestive heart failure.

are 65 years of age or older.

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

are taking insulin or a sulfonylurea medicine.

are pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended-

release tablets can harm your unborn baby. If you are pregnant, talk with your doctor about the best

way to control your blood sugar while you are pregnant.

are a woman who has not gone through menopause (premenopausal) who does not have periods

regularly or at all. Metformin hydrochloride extended-release tablets can cause the release of an

egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant.

are breastfeeding or plan to breastfeed. Metformin hydrochloride can pass into your breast milk.

Talk with your doctor about the best way to feed your baby while you take metformin hydrochloride

extended-release tablets.

Tell your doctor about all the medicines you take, including prescription and over-the-counter

medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them to show

your doctor and pharmacist. Talk to your doctor before you start any 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.

How should I take metformin hydrochloride extended-release tablets?

Take metformin hydrochloride extended-release tablets exactly as your doctor tells you.

Metformin hydrochloride extended-release tablets should be taken 1 time each day with your

evening meal to help decrease an upset stomach.

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

tablets.

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

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

hydrochloride extended-release tablets work.

When your body is under some type 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 doctor

right away if you have any of these problems.

Your doctor should do blood tests to check how well your kidneys are working before and during

your treatment with metformin hydrochloride extended-release tablets.

Your doctor will check your diabetes with regular blood tests, including your blood sugar levels

and your hemoglobin A1C.

Low blood sugar (hypoglycemia) can happen more often when metformin hydrochloride extended-

release tablets is taken with certain other diabetes medicines. Talk to your doctor about how to

prevent, recognize, and manage low blood sugar. See “What are the possible side effects of

metformin hydrochloride extended-release tablets?”.

Check your blood sugar as your doctor 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 at the

normal schedule. Do not take 2 doses of metformin hydrochloride extended-release tablets on the

same day.

If you take too many metformin hydrochloride extended-release tablets, call your doctor 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 possible side effects of metformin hydrochloride extended-release tablets?

Metformin hydrochloride extended-release tablets can cause serious side effects, including:

See “What is the most important information I should know about metformin hydrochloride

extended-release tablets?”

Low vitamin B

(vitamin B

deficiency). Using metformin hydrochloride extended-release

tablets may cause a decrease in the amount of vitamin B

in your blood, especially if you have had

low vitamin B

levels before. Your doctor may do blood tests to check your vitamin B

levels.

Low blood sugar (hypoglycemia). Low blood sugar is a serious, but common, side effect of

metformin hydrochloride extended-release tablets. If you take metformin hydrochloride

extended-release tablets with another medicine that can cause low blood sugar, such as

sulfonylureas or insulin, you have a higher risk of getting low blood sugar. The dose of your

sulfonylurea medicine or insulin may need to be lowered while you take metformin hydrochloride

extended-release tablets. Signs and symptoms of low blood sugar may include:

headache

drowsiness

weakness

irritability

hunger

fast heartbeat

confusion

shaking or feeling jittery

dizziness

12

12

sweating

The most common side effects of metformin hydrochloride extended-release tablets include:

diarrhea

nausea

These are not all of the possible side effects of metformin hydrochloride extended-release tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store metformin hydrochloride extended-release tablets?

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

permitted between 15° and 30°C (59° and 86°F).

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

children.

General information about the safe and effective use of metformin hydrochloride extended-

release tablets.

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 give metformin hydrochloride extended-release tablets to other people, even if they

have the same symptoms you have. It may harm them.

You can ask your pharmacist or doctor for information about metformin hydrochloride extended-release

tablets that is written for health professionals.

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

Active Ingredient: metformin hydrochloride

Inactive Ingredient: anhydrous citric acid, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose,

magnesium stearate, povidone, sodium bicarbonate and sodium lauryl sulfate. The imprinting ink

contains ammonium hydroxide, iron oxide black, N-butyl alcohol, propylene glycol and shellac glaze.

Manufactured for:

Northstar Rx LLC

Memphis, TN 38141.

Manufactured by:

Sun Pharmaceutical Industries Ltd.

Survey No. 259/15, Dadra-396 191,

(U.T. of D & NH), India.

PGPI0376

ISS. 04/2019

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Rx only

NDC 16714-938-01

Once-Daily

Metformin Hydrochloride Extended-Release Tablets, USP

500 mg

100 Tablets

NORTHSTAR

Rx only

NDC 16714-939-01

Once-Daily

Metformin Hydrochloride Extended-Release Tablets, USP

1000 mg

90 Tablets

NORTHSTAR

METFORMIN HYDROCHLORIDE

metformin hydrochloride tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-9 38

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

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

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

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

SO DIUM BICARBO NATE (UNII: 8 MDF5V39 QO)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

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

ETHYLCELLULO SE ( 10 0 MPA.S) (UNII: 47MLB0 F1MV)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

AMMO NIA (UNII: 5138 Q19 F1X)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SHELLAC (UNII: 46 N10 7B71O)

Product Characteristics

Color

WHITE (white to o ff-white)

S core

no sco re

S hap e

ROUND (circular)

S iz e

11mm

Flavor

Imprint Code

30 5

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-9 38 -0 1

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

0 7/25/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 29 17

0 7/25/20 19

METFORMIN HYDROCHLORIDE

metformin hydrochloride tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:16 714-9 39

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

10 0 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

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

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

SO DIUM BICARBO NATE (UNII: 8 MDF5V39 QO)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

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

ETHYLCELLULO SE ( 10 0 MPA.S) (UNII: 47MLB0 F1MV)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

AMMO NIA (UNII: 5138 Q19 F1X)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SHELLAC (UNII: 46 N10 7B71O)

Product Characteristics

Color

WHITE (white to o ff-white)

S core

no sco re

S hap e

ROUND (circular)

S iz e

14mm

Flavor

Imprint Code

30 6

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:16 714-9 39 -0 1

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/25/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 29 17

0 7/25/20 19

Labeler -

NorthStar RxLLC (830546433)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Sun Pharmaceutical Industries

Limite d

6 50 44520 3

ANALYSIS(16 714-9 38 , 16 714-9 39 ) , MANUFACTURE(16 714-9 38 , 16 714-

9 39 )

NorthStar RxLLC

Revised: 7/2019

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