FDA Label for Metformin

Indications & 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.

Dosage And Administration

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride extended-release tablets, USP or any other pharmacologic agent. Dosage of metformin hydrochloride extended-release tablets, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin hydrochloride extended-release tablets, USP in adults is 2000 mg.

Metformin hydrochloride extended-release tablets, USP should generally be given once daily with the evening meal. Metformin hydrochloride extended-release tablets, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin hydrochloride extended-release tablets, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin hydrochloride extended-release tablets, USP either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of metformin hydrochloride extended-release tablets, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Metformin hydrochloride extended-release tablets, USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets, USP will be eliminated in the feces as a soft, hydrated mass. (See Patient Informationprinted below.)

2.1 Adult Dosage

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 are
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 2000 mg once daily with the evening meal.
• If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2000 mg
once daily, consider a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily.
If higher doses are required, switch to metformin hydrochloride tablets at total daily doses up to
2550 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 2000 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 ².
• Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between
30 to 45 mL/minute/ 1.73 m ² is not recommended.
• In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below
45 mL/min/1.73 m ², 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 ² [see Warnings and Precautions (5.1)].

2.4 Discontinuation For Iodinated Contrast Imaging Procedure

Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated
contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m ²; 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.

Dosage Forms And Strengths

Metformin hydrochloride extended-release tablets, USP are available as:
• Extended-release tablets: 500 mg white to off-white uncoated, modified capsule shaped tablets
debossed with "G7" on one side and plain on 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 ²) [see Warnings and Precautions (5.1)].
• Hypersensitivity to metformin.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

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 extendedrelease
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)]:
o Before initiating metformin hydrochloride extended-release tablets, obtain an estimated
glomerular filtration rate (eGFR).
o Metformin hydrochloride extended-release tablets are contraindicated in patients with an

eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].
o Initiation of metformin hydrochloride extended-release tablets are not recommended in
patients with eGFR between 30 to 45 mL/min/1.73 m ².
o Obtain an eGFR at least annually in all patients taking metformin hydrochloride extendedrelease
tablets. In patients at risk for the development of renal impairment (e.g., the elderly),
renal function should be assessed more frequently.
o In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below
45 mL/min/1.73 m ², 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 and 60 mL/min/1.73 m2;
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 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 metforminassociated
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 12 Deficiency

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of
previously normal serum vitamin B ₁₂ levels was observed in approximately 7% of patients. Such decrease,
possibly due to interference with B ₁₂ absorption from the B ₁₂ -intrinsic factor complex, may be associated
with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or
vitamin B ₁₂ supplementation. Certain individuals (those with inadequate vitamin B ₁₂ or calcium intake or
absorption) appear to be predisposed to developing subnormal vitamin B ₁₂ levels. Measure hematologic
parameters on an annual basis and vitamin B ₁₂ 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 B12 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 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 2.

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 3 presents clinically significant drug interactions with metformin hydrochloride extended-release
tablets.

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 2550 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 HbA1C >7 and has been reported to be as high as 20 to 25% in women with a 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 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
2550 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 ²[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:

DESCRIPTION - metformin hcl structure

Metformin hydrochloride, USP is a white to off-white crystalline compound with a molecular formula of
C ₄H ₁₁N ₅ • HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly 4 11 5
soluble in ethanol, practically insoluble in acetone and in methylene chloride. The pKa _{of metformin is 12.4. a
The pH of a 1% aqueous solution of metformin hydrochloride is 6.35.
Metformin hydrochloride extended-release tablets, USP contains 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 tablets contain the inactive ingredients
hypromellose, magnesium stearate, and polyvinyl pyrrolidone
Metformin hydrochloride extended-release tablets USP, 750 mg tablets contain the inactive ingredients
hypromellose, magnesium stearate, and polyvinyl pyrrolidone
Meets USP Dissolution Test 10}

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.

Absorption

Following a single oral dose of metformin hydrochloride extended-release tablets, C _max is achieved with a max
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 _max are less than dose proportional for metformin hydrochloride extended- max
release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are
approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses,
respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride
extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered
as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin
hydrochloride extended-release tablets, metformin did not accumulate in plasma.

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 _max), a 25% lower area under max
the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma
concentration (T _max) following administration of a single 850 mg tablet of metformin hydrochloride tablets max
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 tablet increased by approximately 50% when given with food, there was no effect of
food on C _max and T _max of metformin. Both high and low fat meals had the same effect on the max max
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 4) 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 3) [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 _max
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 4). [see
Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

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

b Peak plasma concentration

c Time to peak plasma concentration

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

e Kinetic study done following dose 19, given fasting

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

g CLcr = creatinine clearance normalized to body surface area of 1.73 m ²

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16).

Race

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

Drug Interactions
In Vivo Assessment of Drug Interactions

* 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 12 hours;
AUC = AUC _0-12h

* 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 _(0.24hr) reported
¶ Ratio of arithmetic means

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 1500 mg/kg/day,
respectively. These doses are both approximately 3 times the maximum recommended human daily dose
of 2550 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 2550 mg
based on body surface area comparisons.

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 _1c of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg
once daily if at Week 12 HbA _1c was ≥7.0% but <8.0% (patients with HbA _1c ≥8.0% were discontinued from
the study). At the final visit (24-week), mean HbA _1c had increased 0.2% from baseline in placebo patients
and decreased 0.6% with metformin hydrochloride extended-release tablets.
A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extendedrelease
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 10.

^aAll comparisons versus Placebo

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 , 1000 mg, 1500 mg, and 2000 mg once daily, 1000 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 11.

^†a n=68
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 1000 mg and 1500 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

16.1 How Supplied

Metformin Hydrochloride Extended-Release Tablets, USP 500mg - White to off white uncoated, modified
capsule shaped tablets debossed with “G7” on one side and plain on other side.

Unit of Use Bottles of 60 Tablets - 500mg - NDC 68645-595-59

16.2 Storage

Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP
Controlled Room Temperature.]
Dispense in light-resistant container.

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)].

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 a
soft mass that may resemble the original tablet.

Dispense with Patient Information is also available at:
http://www.granulesindia.com/U.S.ProductCatalog.php

Manufactured by:
Granules India Limited
Hyderabad-500 081, India

MADE IN INDIA

Manufactured for:
Granules Pharmaceuticals Inc.
Chantilly, VA 20151

Distributed by::
Wal-Mart
Bentonville, AR 72716

Packaged by:
Legacy Pharmaceutical Packaging, LLC
Earth City, MO 63045

Revision date: 10/2021

21890

Patient Information

PATIENT INFORMATION
Metformin Hydrochloride Extended-Release Tablets
(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 extendedrelease
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).
Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets have the same
active ingredient. However, metformin hydrochloride extended-release tablets works longer in your body.
Both of these medicines help control your blood sugar in a number of ways. These include helping your
body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and
decreasing the amount of sugar your intestines absorb. Metformin hydrochloride tablets and 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 extendedrelease
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 extendedrelease
tablet?

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 extended- release
tablets 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 extended-release
tablets 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 works.

Can metformin hydrochloride extended-release tablets be used in children?
Metformin hydrochloride extended-release tablets has 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 works 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 A1C.
• 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 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 extendedrelease
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
hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic
acidosis:
• you feel cold in your hands or feet
• you feel dizzy or lightheaded
• you have a slow or irregular heartbeat
• you feel very weak or tired
• you have 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
dye
• 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 tablet 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 tablet 500 mg:
hypromellose, magnesium stearate, and polyvinyl pyrrolidone.
Inactive ingredients in each tablet of metformin hydrochloride extended-release tablet 750 mg:
hypromellose, magnesium stearate, and polyvinyl pyrrolidone

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.

Dispense with Patient Information is also available at:
http://www.granulesindia.com/U.S.ProductCatalog.php

Manufactured by:
Granules India Limited
Hyderabad-500 081, India
MADE IN INDIA

Manufactured for:
Granules Pharmaceuticals Inc.
Chantilly, VA 20151

Distributed by:
Wal-Mart
Bentonville, AR 72716

Packaged by:
Legacy Pharmaceutical Packaging, LLC
Earth City, MO 63045

Unit of Use Bottles of 60 Tablets - 500mg - NDC 68645-595-59

Revision Date: 10/2021

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