Metformin hydrochloride tablet

Spl unclassified section

Metformin Hydrochloride Tablets , USP
Rx only

Description

Metformin hydrochloridetablets, USPis anoral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride ( N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

The structural formula for Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 HCl and a molecular weight of 165.63. Metformin hydrochloride is

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4H 11N 5HCl and a molecular weight of 165.63. Metformin hydrochlorideis freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK aof metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochlorideis 6.68.

Metformin hydrochloride tablets, USP contain 500 mg, 850 mgor 1,000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg, 850 mg and 1,000 mg tablets contains hypromellose and polyethylene glycol.

Clinical pharmacology

Mechanism of action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS ) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics

Absorption and bioavailability

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1,500mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max), a 25% lower area under 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 with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets850 mg averaged 654 . Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1 ) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific populations

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1 ), nor is there any accumulation of metformin in either group at usual clinical doses.

Renal Impairment

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 1; also see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS ,and DOSAGE AND ADMINISTRATION ).

Hepatic Impairment

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS ).

Geriatrics

Limited data from controlled pharmacokinetic studies of metforminhydrochloride tabletsin healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C maxis increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1 ;also see WARNINGS , PRECAUTIONS ,and DOSAGE AND ADMINISTRATION ).

Table 1: Select Mean (S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets
Subject Groups: M etformin Hydrochloride
Tablets Dose a (number of subjects)
C max b
( mc g/mL)
T max c
(hrs)
Renal Clearance (mL/min)
Healthy, nondiabetic adults:
500 mg single dose (24)
850 mg single dose (74) d
850 mg three times daily for 19 doses e(9)
1.03 (0.33)
1.60 (0.38)
2.01 (0.42)
2.75 (0.81) 2.64 (0.82)
1.79 (0.94)
600 (132)
552 (139)
642 (173)
Adults with type 2 diabetes:
850 mg single dose (23)
850 mg three times daily for 19 doses e(9)
1.48 (0.5)
1.90 (0.62)
3.32 (1.08) 2.01 (1.22) 491 (138)
550 (160)
Elderly f , healthy nondiabetic adults:
850 mg single dose (12)
2.45 (0.70) 2.71 (1.05) 412 (98)
Renal-impaired adults:
850 mg single dose
Mild(CL cr g61to90 mL/min) (5)
Moderate(CL cr31to60 mL/min) (4)
Severe(CL cr10to30 mL/min) (6)
1.86 (0.52)
4.12 (1.83)
3.93 (0.92)
3.20 (0.45) 3.75 (0.50) 4.01 (1.10) 384 (122)
108 (57)
130 (90)

aAll doses given fasting except the first 18 doses of the multiple dose studies
bPeak plasma concentration
cTime to peak plasma concentration
dCombined results (average means) of five studies: mean age 32 years (range 23 to 59 years)
eKinetic study done following dose 19, given fasting
fElderly subjects, mean age 71 years (range 65 to 81 years)
gCLcr = creatinine clearance normalized to body surface area of

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C maxand AUC differed less than 5% between pediatric type 2 diabetic patients (12to 16 years of age) and gender- and weight-matched healthy adults (20to 45 years of age), all with normal renal function.

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride tablets in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical studies

Metformin Hydrochloride Tablets

In a double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin (up to 2,550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A (HbA) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).

Table 2: Metformin vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)
M etformin
(n = 141)
Placebo
(n = 145)
p-Value
FPG (mg/dL)
Baseline
Change at FINAL VISIT
241.5
53.0
237.7
6.3
NS**
0.001
Hemoglobin A (%)
Baseline
Change at FINAL VISIT
8.4
1.4
8.2
0.4
NS**
0.001
Body Weight (lbs)
Baseline
Change at FINAL VISIT
201.0
1.4
206.0
2.4
NS**
NS**

* All patients on diet therapy at Baseline** Not statistically significant

A 29-week, double-blind, placebo-controlled study of metformin and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with metformin 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of metformin increased by 500mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin 2,500 mg. Patients in the metformin only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin 2,000 mg/glyburide 20 mg or metformin 2,500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA of 14 mg/dL, 3mg/dL, and 0.2%, respectively. In contrast, those randomized to metformin (up to 2,500mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of metformin and glyburide was effective in reducing FPG, PPG, and HbA levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were 77 mg/dL, 68 mg/dL, and 1.9%, respectively (see Table 3).

Table 3: Combined Metformin /Glyburide (Comb) vs Glyburide (Glyb) or Metformin (Met) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)
p-values
Comb
(n
= 213)
Glyb
(n
= 209)
Met
(n
= 210)
Glyb vs
Comb
Met vs
Comb
Met vs
Glyb
Fasting Plasma Glucose (mg/dL)
Baseline
Change at FINAL VISIT
250.5
63.5
247.5
13.7
253.9
0.9
NS**
0.001
NS**
0.001
NS**
0.025
Hemoglobin A (%)
Baseline
Change at FINAL VISIT
8.8
1.7
8.5
0.2
8.9
0.4
NS**
0.001
NS**
0.001
0.007
0.001
Body Weight (lbs)
Baseline
Change at FINAL VISIT
202.2
0.9
203.0
0.7
204.0
8.4
NS**
0.011
NS**
0.001
NS**
0.001

* All patients on glyburide, 20 mg/day, at Baseline** Not statistically significant

The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablet therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, metformin, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels, and had no adverse effects on other lipid levels (see Table 4).

Table 4: Summary of Mean Percent Change From Baseline of Major Serum Lipid Variables at Final Visit (29-week studies)
M etformin vs Placebo Combined M etformin /Glyburide vs Monotherapy
M etformin
(n = 141)
Placebo
(n = 145)
M etformin
(n = 210)
M etformin /Glyburide
(n = 213)
Glyburide
(n = 209)
Total Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
211.0
5%
212.3
1%
213.1
2%
215.6
4%
219.6
1%
Total Triglycerides (mg/dL)
Baseline
Mean % Change at FINAL VISIT
236.1
16%
203.5
1%
242.5
3%
215.0
8%
266.1
4%
LDL-Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
135.4
8%
138.5
1%
134.3
4%
136.0
6%
137.5
3%
HDL-Cholesterol (mg/dL)
Baseline
Mean % Change at FINAL VISIT
39.0
2%
40.5
1%
37.2
5%
39.0
3%
37.0
1%

In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 2and 3).

A 24-week, double-blind, placebo-controlled study of metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive metformin plus insulin achieved a reduction in HbA of 2.10%, compared to a 1.56% reduction in HbA achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p=0.04.

Table 5: Combined Metformin /Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
M etformin
/Insulin
(n = 26)
Placebo/
Insulin
(n = 28)
Treatment
Difference
Mean SE
Hemoglobin A (%)
Baseline
Change at FINAL VISIT

8.95
-2.10

9.32
-1.56

-0.54
Insulin Dose (U/day)
Baseline
Change at FINAL VISIT

93.12
-0.15

94.64
15.93

-16.08 7.77 b

aStatistically significant using analysis of covariance with baseline as covariate (p=0.04)
Not significant using analysis of variance (values shown in table)
bStatistically significant for insulin (p=0.04)

A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA of 7.46 0.97%, the addition of metformin maintained similar glycemic control (HbA 7.15 0.61 vs 6.97 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 30.22 vs an increase of 0.43 25.20 units for metformin plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 , compared to an increase of 1.30 for placebo plus insulin, p=0.01.

Pediatric clinical studies

In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 6).

Table 6: Metformin vs Placebo (Pediatrics a) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit
M etformin Placebo p-Value
FPG (mg/dL)
Baseline
Change at FINAL VISIT
(n = 37)
162.4
-42.9
(n = 36)
192.3
21.4


<0.001
Body Weight (lbs)
Baseline
Change at FINAL VISIT
(n = 39)
205.3
-3.3
(n = 38)
189.0
-2.0


NS**

aPediatric patients mean age 13.8 years (range 10 to 16 years)
*All patients on diet therapy at Baseline
**Not statistically significant

Indications and usage

Metformin hydrochloride tabletsare indicated as an adjunct to diet and exercise to improve glycemic control in adultsand children with type 2 diabetes mellitus.

Contraindications

Metformin hydrochloridetablets are contraindicated in patients with:

  1. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2)(see WARNINGS and PRECAUTIONS ).
  2. Known hypersensitivity to metformin hydrochloride.
  3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Warnings

Warning: lactic acidosis

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 PRECAUTIONS ).

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see DOSAGE AND ADMINISTRATION , CONTRAINDICATIONS , and PRECAUTIONS ).

If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).

Precautions

General

  • Lactic acidosisThere 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.
    Ifmetformin-associatedlacticacidosisissuspected,generalsupportivemeasuresshouldbe instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride tablets. In metformin hydrochloride tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysisis recommended to correct the acidosis and remove accumulated metformin(metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under goodhemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms andrecovery.
    Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride tablets and report these symptoms to their healthcare provider.
    For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
  • Renal impairmentThe 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 patients renal function include (see DOSAGE AND ADMINISTRATION , CLINICAL PHARMACOLOGY ):
    Before initiating metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR)
    Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 (see CONTRAINDICATIONS ).
    Initiation of metformin hydrochloride tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
    Obtain an eGFR at least annually in all patients taking metformin hydrochloride tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
    In patients taking metformin hydrochloride tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
  • Drug interactionsTheconcomitantuseofmetformin hydrochloride tabletswith specific drugs may increase the risk of metformin-associated lactic acidosis: those thatimpair renal function, result in significant hemodynamic change, interfere with acid-base balance,or increase metformin accumulation. Consider more frequent monitoring ofpatients.
  • Age 65 or greaterThe risk of metformin-associated lactic acidosis increases withthe patientsagebecauseelderlypatientshaveagreaterlikelihoodofhavinghepatic,renal,or cardiacimpairmentthanyoungerpatients.Assessrenalfunctionmorefrequentlyinelderly patients.
  • Radiologic studies with contrastAdministration of intravascular iodinated contrastagents in metformin-treated patients has led to an acute decrease in renal function andthe occurrence of lactic acidosis. Stop metformin hydrochloride tablets at the time of,or priorto,aniodinatedcontrastimagingprocedureinpatientswithaneGFRbetween30and 60mL/min/1.73m 2;inpatientswithahistoryofhepaticimpairment,alcoholismorheart failure; or in patients who will be administered intra-arterial iodinated contrast.Re-evaluateeGFR 48 hours after the imaging procedure, and restart metformin hydrochloride tablets if renal function isstable.
  • Surgery and other proceduresWithholdingoffoodandfluidsduringsurgicalorother proceduresmayincreasetheriskforvolumedepletion,hypotension,andrenalimpairment. Metformin hydrochloride tablets should be temporarily discontinued whilepatients have restricted food and fluid intake.
  • Hypoxic statesSeveral of the postmarketing cases of metformin-associated lacticacidosis occurredinthesettingofacutecongestiveheartfailure(particularlywhenaccompaniedby hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acutemyocardial infarction, sepsis, and other conditions associated with hypoxemia have been associatedwith lacticacidosisandmaycauseprerenalazotemia.Whensuchaneventoccurs,discontinue metformin hydrochloride tablets.
  • Excessive a lcohol intakeAlcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metforminhydrochloride tablets.
  • Hepatic impairmentPatients with hepatic impairment have developed cases ofmetformin-associatedlacticacidosis.Thismaybeduetoimpairedlactateclearanceresultinginhigherlactatebloodlevels.Therefore,avoiduseofmetforminhydrochloride tabletsin patients with clinical or laboratory evidence of hepaticdisease.

Vitamin B 12 levelsIn controlled clinical trials of metformin hydrochloride tabletsof 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12absorption from the B 12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metforminhydrochloride tabletsor vitamin B 12supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride tablets and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS : Laboratory Tests ).

Certain individuals (those with inadequate vitamin B 12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12levels. In these patients, routine serum vitamin B 12measurements at 2- to 3-year intervals may be useful.

HypoglycemiaHypoglycemia does not occur in patients receiving metformin hydrochloride tablets alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Macrovascular outcomesThere have been no clinical studies establishing conclusiveevidence ofmacrovascularriskreductionwithmetformin hydrochloride tabletsoranyother antidiabeticdrug.

Information for patients

Patients should be informed of the potential risks and benefits of metforminhydrochloride tabletsand of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue metforminhydrochloride tabletsimmediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of metforminhydrochloride tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving metforminhydrochloride tablets.

Metforminhydrochloride tabletsalone do not usually cause hypoglycemia, although it may occur when metforminhydrochloride tabletsare used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)

Laboratory tests

Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION ).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metforminhydrochloride tabletstherapy, if this is suspected, vitamin B 12deficiency should be excluded.

Instruct patients to inform their doctor that they are taking metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuationof metformin hydrochloride tablets may be required until renal function hasbeen confirmed to be normal (see PRECAUTIONS ).

Drug interactions (clinical evaluation of drug interactions conducted with m etformin hydrochloride tablets )

GlyburideIn a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C maxwere observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION : Concomitant Metformin Hydrochloride Tablets and Oral Sulfonylurea Therapy in Adult Patients ).

FurosemideA single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C maxby 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C maxand AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

NifedipineA single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C maxand AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T maxand half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Drugs that reduce metformin clearanceConcomitant use of drugs that interfere withcommon renaltubulartransportsystemsinvolvedintherenaleliminationofmetformin(e.g.,organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors suchas ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposureto metformin and may increase the risk for lactic acidosis. Consider the benefits and risksof concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

Inhealthyvolunteers,thepharmacokineticsofmetforminandpropranolol,andmetforminand ibuprofen were not affected when coadministered in single-dose interactionstudies.

Metforminisnegligiblyboundtoplasmaproteinsandis,therefore,lesslikelytointeractwith highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, andprobenecid, as compared to the sulfonylureas, which are extensively bound to serumproteins.

OtherCertain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metforminhydrochloride tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metforminhydrochloride tablets, the patient should be observed closely for hypoglycemia.

Carbonic anhydrase inhibitorsTopiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease inserum bicarbonateandinducenon-aniongap,hyperchloremicmetabolicacidosis.Concomitantuseof these drugs with metformin hydrochloride tablets may increase the risk forlactic acidosis. Consider more frequent monitoring of thesepatients.

AlcoholAlcoholisknowntopotentiatetheeffectofmetforminonlactatemetabolism.Warn patients against excessive alcohol intake while receiving metformin hydrochloride tablets.

Carcinogenesis, mutagenesis, impairment of fertility

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500mg/kg/day, respectively. These doses are both approximately 4 times 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 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 vitrotests: Ames test ( S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vi vomouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy

Teratogenic effects: pregnancy category b

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, metformin hydrochloride tabletsshould not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with metforminhydrochloride tablets. Metformin was not teratogenic in rats and rabbits at doses up to 600mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing mothers

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If metforminhydrochloride tabletsarediscontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric use

The safety and effectiveness of metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of metformin in this age group is supported by evidence from adequate and well-controlled studies of metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY : Pediatric Clinical Studies .) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS : Pediatric Patients .) A maximum daily dose of 2,000 mg is recommended. (See DOSAGE AND ADMINISTRATION : Recommended Dosing Schedule: Pediatrics .)

Geriatric use

Controlled clinical studies of metforminhydrochloride tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the lowend of the dosing range, reflecting the greater frequency of decreased hepatic, renal, orcardiacfunction, and of concomitant disease or other drug therapy and the higher risk of lacticacidosis. Assess renal function more frequently in elderly patients (see WARNINGS , PRECAUTIONS ,and DOSAGE ANDADMINISTRATION ).

Adverse reactions

In a US double-blind clinical study of metforminhydrochloride tabletsin patients with type 2 diabetes, a total of 141 patients received metforminhydrochloride tablets therapy (up to 2,550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metforminhydrochloride tablets patients, and that were more common in metforminhydrochloride tablets- than placebo-treated patients, are listed in Table 7.

Table 7: Most Common Adverse Reactions (>5.0 Percent) in a Placebo-Controlled Clinical Study of Metformin Hydrochloride Tablets Monotherapy*
Adverse Reaction M etformin Monotherapy
(n = 141)
Placebo
(n = 145)
% of Patients
Diarrhea 53.2 11.7
Nausea/Vomiting 25.5 8.3
Flatulence 12.1 5.5
Asthenia 9.2 5.5
Indigestion 7.1 4.1
Abdominal Discomfort 6.4 4.8
Headache 5.7 4.8

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

Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in 1.0% to 5.0% of metforminhydrochloride tabletspatients and were more commonly reported with metforminhydrochloride tabletsthan placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reportedwith postmarketing use ofmetformin.

Pediatric patients

In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Overdosage

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Dosage and administration

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metforminhydrochloride tabletsor any other pharmacologic agent. Dosage of metformin hydrochloride tabletsmust be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin hydrochloride tablets is 2,550 mg in adults and 2,000 mg in pediatric patients (10 to 16 years of age).

Metformin hydrochloride tabletsshould be given in divided doses with meals and 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 tabletsand 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 m etformin hydrochloride tablets , either when used as monotherapy or in combination with sulfonylurea or insulin.

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

Short-term administration of metforminhydrochloride tabletsmay be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Recommendations for use in renal impairment

Assess renal function prior to initiation of metformin hydrochloride tabletsand periodicallythereafter.

Metformin hydrochloride tabletsare contraindicated in patients with anestimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73m 2.

Initiation of metformin hydrochloride tablets in patients with an eGFR between 30 to45 mL/minute/1.73 m 2 is notrecommended.

In patients taking metformin hydrochloride tablets whose eGFR later falls below45 mL/min/1.73 m 2, assess the benefit risk of continuingtherapy.

Discontinue metformin hydrochloride tablets if the patients eGFR later falls below30 mL/minute/1.73 m 2 (See WARNINGS and PRECAUTIONS ).

Discontinuation for iodinated contrast imaging procedures

Discontinuemetformin hydrochloride tabletsatthetimeof,orpriorto,aniodinated contrastimagingprocedureinpatientswithaneGFRbetween30and60mL/min/1.73m 2;in patientswithahistoryofliverdisease,alcoholism,orheartfailure;orinpatientswhowillbe administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after theimaging procedure; restart metformin hydrochloride tablets if renal function isstable.

Concomitant m etformin hydrochloride tablets and oral sulfonylurea therapy in adult patients

If patients have not responded to 4 weeks of the maximum dose of metforminhydrochloride tabletsmonotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metforminhydrochloride tabletsat the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).

With concomitant metformin hydrochloride tabletsand sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metforminhydrochloride tablets 500 mg and glyburide 20 mg were titrated to 1,000/20 mg, 1,500/20 mg, 2,000/20 mg, or 2,500/20 mg of metformin hydrochloride tabletsand glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA, and plasma glucose response (see CLINICAL PHARMACOLOGY : Clinical Studies ). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin hydrochloride tabletsand sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)

If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of metformin hydrochloride tabletsand the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metforminhydrochloride tablets.

Concomitant m etformin hydrochloride tablets and insulin therapy in adult patients

The current insulin dose should be continued upon initiation of metformin hydrochloride tabletstherapy. Metforminhydrochloride tablets therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metforminhydrochloride tablets should be increased by 500mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2,500 mg for metforminhydrochloride tablets. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metforminhydrochloride tablets. Further adjustment should be individualized based on glucose-lowering response.

Specific patient populations

Metformin hydrochloride tabletsarenot recommended for use in pregnancy. Metforminhydrochloride tabletsarenot recommended in patients below the age of 10 years.

The initial and maintenance dosing of metformin hydrochloride tabletsshould be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function.

How supplied

Metformin hydrochloride tablets USP, 500 mgare roundwhite tablets, debossed with500 on one side.

They are available as follows:

Bottles of 100 NDC 58657-640-01
Bottles of 500 NDC 58657-640-50
Bottles of 1000 NDC 58657-640-10

Metformin hydrochloride tablets USP, 85 0 mgare roundwhite tablets, debossed with850 on one side.

They are available as follows:

Bottles of 100 NDC 58657-641-01
Bottles of 500 NDC 58657-641-50
Bottles of 1000 NDC 58657-641-10

Metformin hydrochloride tablets USP, 1 , 00 mgare oval white tablets, debossed with10|00 on one side.

They are available as follows:

Bottles of 100 NDC 58657-642-01
Bottles of 500 NDC 58657-642-50
Bottles of 1000 NDC 58657-642-10

Storage

Store at 20 to 25C (68 to 77F); excursions permitted to15 to 30C (59 to 86F). [See USP Controlled Room Temperature.]

Dispense in tight, light-resistant containers.

Manufactured by:
CSPC Ouyi Pharmaceutical Co., Ltd.
Shijiazhuang, Hebei, China052160

Manufactured for:
Method Pharmaceuticals, LLC
Fort Worth, TX 76118

Rev. 06/2017

Spl patient package insert section

P ATIENT INFORMATION
M ETFORMIN HYDROCHLORIDE TABLETS, USP
(met for min hye droe klor ide)

Read this information carefully before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of your doctors advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.

What are m etformin hydrochloride tablets ?

Metforminhydrochloride tablets areused to treat type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take metforminhydrochloride tablets, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness.

Metforminhydrochloride tablets help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metforminhydrochloride tabletsdo not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain.

Tell your doctor if you are pregnant or plan to become pregnant. Metforminhydrochloride tablets may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child.

Can m etformin hydrochloride tablets be used in children?

Metformin hydrochloride tablets havebeen shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. Metforminhydrochloride tabletshavenot been studied in children younger than 10 years old. Metformin hydrochloride tablets havenot been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of metformin hydrochloride tablets in children, talk with your doctor or other healthcare provider.

How should I take m etformin hydrochloride tablets ?

Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metforminhydrochloride tabletswith meals.

Your doctor may have you take other medicines along with metforminhydrochloride tabletsto control your blood sugar. These medicines may include insulin shots. Taking metforminhydrochloride tabletswith insulin may help you better control your blood sugar while reducing the insulin dose.

Continue your exercise and diet program and test your blood sugar regularly while taking metforminhydrochloride tablets. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that metforminhydrochloride tabletscause harm to the liver or kidneys.

Tell your doctor if you:

  • have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking metformin hydrochloride tabletsfor a short time.
  • plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin hydrochloride tabletsfor a short time.
  • start to take other medicines or change how you take a medicine. Metforminhydrochloride tabletscan affect how well other drugs work, and some drugs can affect how well metformin hydrochloride tablets work. Some medicines may cause high blood sugar.

What should I avoid while taking m etformin hydrochloride tablets ?

Do not drink a lot of alcoholic drinks while taking metforminhydrochloride 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 m etformin hydrochloride tablets ?

  • Lactic acidosis. Metformin, the active ingredient in m etformin h ydrochloride 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 signsof lacticacidosis:

  • you feel cold in your hands orfeet
  • you feel dizzy or lightheaded
  • you have a slow or irregular heartbeat
  • you feel very weak or tired
  • you have unusual (not normal) muscle pain
  • you have trouble breathing
  • you feel sleepy or drowsy
  • you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combinedwith themetformin,ledtothelacticacidosis.Tellyourdoctorifyouhaveanyofthefollowing, because you have a higher chance for getting lactic acidosis with metformin hydrochloridetablets ifyou:

  • haveseverekidneyproblems,oryourkidneysareaffectedbycertainx-rayteststhatuse injectabledye
  • 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

Thebestwaytokeepfromhavingaproblemwithlacticacidosisfrommetforministotellyour doctorifyouhaveanyoftheproblemsinthelistabove.Yourdoctormaydecidetostopyour metformin hydrochloride tablets for a while if you have any of thesethings.

Other Side Effects. Common side effects of metforminhydrochloride tabletsinclude 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 theyve 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 metforminhydrochloride tabletshave an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

Metformin hydrochloride tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.

General advice about prescription medicines

If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metforminhydrochloride tabletsthat is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metforminhydrochloride tabletsfor a condition for which it was not prescribed. Do not share your medicine with other people.

Manufactured by:
CSPC Ouyi Pharmaceutical Co., Ltd.
Shijiazhuang, Hebei, China, 052160

Manufactured for:
Method Pharmaceuticals, LLC
Fort Worth, TX 76118

Rev. 06/2017

Ingredients and appearance - Product information

Metformin hydrochloride tablet- Metformin hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 58657-640
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Metformin hydrochloride ( UNII: 786Z46389E)( Metformin - UNII: 9100L32L2N ) 500 mgin 1

Inactive Ingredients

Ingredient Name Code
Povidone ( UNII: FZ989GH94E)
Magnesium stearate ( UNII: 70097M6I30)
Hypromelloses ( UNII: 3NXW29V3WO)
Polyethylene glycol, unspecified ( UNII: 3WJQ0SDW1A)

Product Characteristics

Color white Imprint Code 500
Score 1 Shape ROUND
Size 11 mm

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 58657-640-01 100 in 1 BOTTLE 2017/03/15
2 NDC: 58657-640-50 500 in 1 BOTTLE 2017/03/15
3 NDC: 58657-640-10 1000 in 1 BOTTLE 2017/03/15

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA205096 USA 2017/03/15

Metformin hydrochloride tablet- Metformin hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 58657-641
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Metformin hydrochloride ( UNII: 786Z46389E)( Metformin - UNII: 9100L32L2N ) 850 mgin 1

Inactive Ingredients

Ingredient Name Code
Povidone ( UNII: FZ989GH94E)
Magnesium stearate ( UNII: 70097M6I30)
Hypromelloses ( UNII: 3NXW29V3WO)
Polyethylene glycol, unspecified ( UNII: 3WJQ0SDW1A)

Product Characteristics

Color white Imprint Code 850
Score 1 Shape ROUND
Size 13 mm

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 58657-641-01 100 in 1 BOTTLE 2017/03/15
2 NDC: 58657-641-50 500 in 1 BOTTLE 2017/03/15
3 NDC: 58657-641-10 1000 in 1 BOTTLE 2017/03/15

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA205096 USA 2017/03/15

Metformin hydrochloride tablet- Metformin hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 58657-642
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Metformin hydrochloride ( UNII: 786Z46389E)( Metformin - UNII: 9100L32L2N ) 1000 mgin 1

Inactive Ingredients

Ingredient Name Code
Povidone ( UNII: FZ989GH94E)
Magnesium stearate ( UNII: 70097M6I30)
Hypromelloses ( UNII: 3NXW29V3WO)
Polyethylene glycol, unspecified ( UNII: 3WJQ0SDW1A)

Product Characteristics

Color white Imprint Code 10;00
Score 1 Shape OVAL
Size 19 mm

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 58657-642-01 100 in 1 BOTTLE 2017/03/15
2 NDC: 58657-642-50 500 in 1 BOTTLE 2017/03/15
3 NDC: 58657-642-10 1000 in 1 BOTTLE 2017/03/15

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA205096 USA 2017/03/15

Labeler - Method Pharmaceuticals, LLC( 060216698)

Principal display panel

NDC 58657- 640-01
M etformin H ydrochloride
T
ablets , USP
500 mg

100 Tablets
Rx Only

Principal display panel

NDC 58657- 64 1-01
M etformin H ydrochloride
T
ablets , USP
850 mg

100 Tablets
Rx Only

Principal display panel

NDC 58657- 64 2-01
M etformin H ydrochloride
T
ablets , USP
1000 mg

100 Tablets
Rx Only