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Metformin Hydrochloride

State of Florida DOH Central Pharmacy

Metformin Hydrochloride Tablets, USP


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

METFORMIN HYDROCHLORIDE DESCRIPTION


N,N-
Metformin Hydrochloride
4115a

CLINICAL PHARMACOLOGY

Mechanism of Action


PRECAUTIONS

Pharmacokinetics

Absorption and Bioavailability


maxmax

Distribution


Metabolism and Elimination


Table 1

Special Populations

Patients with Type 2 Diabetes


Table 1

Renal Insufficiency


Table 1 WARNINGS

Hepatic Insufficiency


Geriatrics


maxTable 1 WARNINGS  DOSAGE AND ADMINISTRATION
Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of  Metformin Hydrochloride Tablets
Subject Groups:  Metformin
Hydrochloride Tablets
dosea (number of subjects)		 Cmax b (mcg/mL) Tmax c (hrs) Renal
Clearance
(mL/min)
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 to 59 years)
e Kinetic study done following dose 19, given fasting
f Elderly subjects, mean age 71 years (range 65 to 81 years)
g CLcr = creatinine clearance normalized to body surface area of 1.73 m2
 Healthy, nondiabetic adults:
   500 mg single dose (24)
   850 mg single dose (74)d
   850 mg three times daily for 19 dosese (9)  

1.03 (±0.33)
1.6 (±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 dosese (9) 

1.48 (±0.5)
1.9 (±0.62)
   3.32 (±1.08)   
   2.01 (±1.22)   
   491 (±138)   
   550 (±160)   
 Elderlyf, healthy nondiabetic adults:
   850 mg single dose (12)
2.45 (±0.7)
   2.71 (±1.05)   
   412 (±98)   
 Renal-impaired adults:
  850 mg single dose
    Mild (CLcr g 61 to 90 mL/min) (5)
    Moderate (CLcr 31 to 60 mL/min) (4)
    Severe (CLcr 10 to 30 mL/min) (6)
 
1.86 (±0.52)
4.12 (±1.83)
3.93 (±0.92)
 
   3.2 (±0.45)   
   3.75 (±0.5)   
   4.01 (±1.1)   
 
   384 (±122)   
   108 (±57)   
   130 (±90)   

Pediatrics


max

Gender


Race


Clinical Studies


1c1cTable 2


Table 2: Metformin Hydrochloride Tablets vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)
Metformin 
   Hydrochloride    
Tablets
(n = 141)		    Placebo   
   (n = 145)   		    p–Value   
*All patients on diet therapy at Baseline         
**Not statistically significant
 FPG (mg/dL)
    Baseline
    Change at FINAL VISIT
241.5
-53
237.7
6.3
NS**
0.001
 Hemoglobin A1c (%)
    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
-1.4
206
-2.4
NS **
NS **

Table 31c 1c 1c Table 3
Table 3:  Combined Metformin Hydrochloride Tablets/Glyburide (Comb) vs Glyburide (Glyb) or Metformin Hydrochloride Tablets (MET) Monotherapy: Summary  of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study) 
Comb
   (n = 213)   		 Glyb
   (n = 209)   		 MET
   (n =210)   		 p-values
   Glyb vs   
Comb		    MET vs   
Comb		    MET vs   
Glyb
*   All patients on glyburide, 20 mg/day, at Baseline           
** Not statistically significant
 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 A1c (%)
   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
-0.7
204
-8.4
NS**
0.011
NS**
0.001
NS**
0.001



Table 4
Table 4:  Summary of Mean Percent Change From Baseline of Major Serum Lipid Variables at Final Visit (29-week studies)
   Metformin Hydrochloride   
Tablets vs Placebo		    Combined Metformin Hydrochloride   
Tablets/Glyburide vs Monotherapy
Metformin
Hydrochloride
Tablets
(n = 141)		 Placebo
(n = 145)		 Metformin
  Hydrochloride 
Tablets
(n = 210)		 Metformin
  Hydrochloride 
Tablets/
Glyburide
(n = 213)		   Glyburide 
(n = 209)
 Total Cholesterol (mg/dL)
   Baseline
   Mean % Change at FINAL VISIT 

 211 
-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 
-8%
 266.1 
4%
 LDL-Cholesterol (mg/dL)
   Baseline
   Mean % Change at FINAL VISIT
 135.4 
-8%
 138.5 
1%
 134.3 
-4%
 136 
-6%
137.5 
3%
 
  
  
  
  
  
 HDL Cholesterol (mg/dL)
   Baseline
   Mean % Change at FINAL VISIT
 39 
2%
 40.5 
-1%
 37.2 
5%
 39 
3%
 37 
1%

Tables 2 3

Table 51c1c
Table 5: Combined Metformin Hydrochloride Tablets/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
Metformin
Hydrochloride
Tablets/Insulin
(n=26)		 Placebo/
Insulin
(n=28)		 Treatment
Difference
Mean ± SE
a   Statistically significant using analysis of covariance with baseline as covariate (p=0.04)
   Not significant using analysis of variance (values shown in table)
b  Statistically significant for insulin (p=0.04)
 Hemoglobin A1c (%)
   Baseline
   Change at FINAL VISIT
8.95
-2.1
9.32
-1.56

-0.54 ± 0.43a
 Insulin Dose (U/day)
   Baseline
   Change at FINAL VISIT
93.12
-0.15
94.64
15.93

-16.08 ± 7.77b

1c1c

Pediatric Clinical Studies


Table 6
Table 6: Metformin Hydrochloride Tablets vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline* in Plasma Glucose and Body weight at Final Visit
Metformin
   Hydrochloride   
Tablets		    Placebo       p-Value   
a  Pediatric patients mean age 13.8 years (range 10 to 16 years)
*  All patients on diet therapy at Baseline
** Not statistically significant
  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
-2
 
NS**

METFORMIN HYDROCHLORIDE INDICATIONS AND USAGE


METFORMIN HYDROCHLORIDE CONTRAINDICATIONS



  • Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS .)
  • Known hypersensitivity to metformin hydrochloride.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. 
     

Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS .)

WARNINGS

Lactic Acidosis


Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases.  Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.  Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin.  In particular, treatment of the elderly should be accompanied by careful monitoring of renal function.  Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.  Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin hydrochloride tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The  patient and  the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Metformin hydrochloride tablets should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin.  Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)

PRECAUTIONS

General


Macrovascular Outcomes—

Monitoring of renal function— WARNINGS  DOSAGE AND ADMINISTRATION



Use of concomitant medications that may affect renal function or metformin disposition— PRECAUTIONS: Drug Interactions

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous  urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)— CONTRAINDICATIONS

Hypoxic states—

Surgical procedures

Alcohol intake

Impaired hepatic function

Vitamin B12 levels12 121212 PRECAUTIONS: Laboratory Tests

121212

Change in clinical status of patients with previously controlled type 2 diabetes WARNINGS

Hypoglycemia



Loss of control of blood glucose—

Information for Patients




WARNINGS PRECAUTIONS



Patient Information

Laboratory Tests


DOSAGE AND ADMINISTRATION

12

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted With Metformin Hydrochloride Tablets)


Glyburide—max DOSAGE AND ADMINISTRATION: Concomitant Metformin and Oral Sulfonylurea Therapy in Adult Patients

Furosemide—max max

Nifedipine—maxmax

Cationic drugs—

Other—



Carcinogenesis, Mutagenesis, Impairment of Fertility






in vitro S. typhimuriumin vivo

Pregnancy

Teratogenic effects






Nursing Mothers


Pediatric Use


CLINICAL PHARMACOLOGY: Pediatric Clinical Studies ADVERSE REACTIONS: Pediatric Patients. DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.

Geriatric Use


CONTRAINDICATIONS, WARNINGS, CLINICAL PHARMACOLOGY: Pharmacokinetics WARNINGS DOSAGE AND ADMINISTRATION

METFORMIN HYDROCHLORIDE ADVERSE REACTIONS


Table 7
Table 7: Most Common Adverse Reactions (>5 Percent) in a Placebo-Controlled Clinical Study of Metformin Hydrochloride Tablets Monotherapy*
Adverse Reaction Metformin
   Hydrochloride   
Tablets
Monotherapy
(n = 141)		    Placebo   
   (n = 145)   
% of Patients
*  Reactions that were more common in metformin
    hydrochloride tablets- than placebo-treated 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

Pediatric Patients


OVERDOSAGE


WARNINGS

METFORMIN HYDROCHLORIDE DOSAGE AND ADMINISTRATION






Recommended Dosing Schedule 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, either when used as monotherapy or in combination with sulfonylurea or insulin.



Recommended Dosing Schedule


Adults -



Pediatrics –

Transfer From Other Antidiabetic Therapy


Concomitant Metformin and Oral Sulfonylurea Therapy in Adult Patients




1c CLINICAL PHARMACOLOGY: Clinical Studies

Concomitant Metformin and Insulin Therapy in Adult Patients


Specific Patient Populations






WARNINGS

HOW SUPPLIED




500 mg Tablets:

850 mg Tablets:

1000 mg Tablets:

They are supplied by State of Florida DOH Central Pharmacy as follows:

NDC Strength Quantity/Form Color Source Prod. Code
53808-0459-1 850 mg 30 Tablets in a Blister Pack WHITE 65862-009
Storage



Patient Information

Metformin Hydrochloride Tablets, USP


Rx only

What is metformin?








WARNING: A small number of people who have taken metformin hydrochloride tablets have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most people with kidney problems should not take metformin.  (See “What are the side effects of metformin?”)

Who should not take metformin?




Do not take metformin if you:

 

  • have kidney problems
  • have liver problems
  • have heart failure that is treated with medicines, such as Lanoxin® (digoxin) or Lasix® (furosemide)
  • drink a lot of alcohol. This means you binge drink for short periods or drink all the time
  • are seriously dehydrated (have lost a lot of water from your body)
  • are going to have an x-ray procedure with injection of dyes (contrast agents)
  • are going to have surgery
  • develop a serious condition, such as heart attack, severe infection, or a stroke
  • are 80 years or older and you have NOT had your kidney function tested

Can metformin hydrochloride tablets be used in children?


How should I take metformin hydrochloride tablets?








 

  • 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 for a short time.
  • plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin hydrochloride tablets for a short time.
  • start to take other medicines or change how you take a medicine. Metformin can affect how well other drugs work, and some drugs can affect how well metformin work. Some medicines may cause high blood sugar.

What should I avoid while taking metformin hydrochloride tablets?


What are the side effects of metformin?


Lactic Acidosis. In rare cases, metformin can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This buildup can cause serious damage.



stop using metformin and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital.

Signs of lactic acidosis are:

 

  • feeling very weak, tired, or uncomfortable
  • unusual muscle pain
  • trouble breathing
  • unusual or unexpected stomach discomfort
  • feeling cold
  • feeling dizzy or lightheaded
  • suddenly developing a slow or irregular heartbeat

 




Other Side Effects.



General advice about prescription medicines





Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 1000 mg (50 Tablet Bottle)


NDC 53808-0459-1
Metformin Hydrochloride Tablets, USP
850 mg
Rx only           30 Tablets
AUROBINDO
Metformin Hydrochloride

Metformin Hydrochloride

Metformin Hydrochloride TABLET, FILM COATED

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:53808-0459(NDC:65862-009)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
METFORMIN HYDROCHLORIDE METFORMIN 850 mg

Inactive Ingredients

Ingredient Name Strength
POVIDONE K90
MAGNESIUM STEARATE
HYPROMELLOSE 2910 (5 CPS)
polyethylene glycol 400
polyethylene glycol 6000

Product Characteristics

Color Size Imprint Code Shape
WHITE 13 mm A;13 ROUND

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:53808-0459-1 30 in 1 BLISTER PACK

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077095 2009-07-01


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