Metformin Hydrochloride
Metformin Hydrochloride Tablets, USP
FULL PRESCRIBING INFORMATION: CONTENTS*
- METFORMIN HYDROCHLORIDE DESCRIPTION
- CLINICAL PHARMACOLOGY
- METFORMIN HYDROCHLORIDE INDICATIONS AND USAGE
- METFORMIN HYDROCHLORIDE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- METFORMIN HYDROCHLORIDE ADVERSE REACTIONS
- OVERDOSAGE
- METFORMIN HYDROCHLORIDE DOSAGE AND ADMINISTRATION
- HOW SUPPLIED
- Patient Information
- Metformin Hydrochloride Tablets, USP
- What is metformin?
- Who should not take metformin?
- Can metformin hydrochloride tablets be used in children?
- How should I take metformin hydrochloride tablets?
- What should I avoid while taking metformin hydrochloride tablets?
- What are the side effects of metformin?
- General advice about prescription medicines
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg (100 Tablet Bottle)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg Bulk Tablet Label
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 850 mg (100 Tablet Bottle)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 850 mg Bulk Tablet Label
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 1000 mg (100 Tablet Bottle)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 1000 mg Bulk Tablet Label
FULL PRESCRIBING INFORMATION
METFORMIN HYDROCHLORIDE DESCRIPTION
N,N-
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
| 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
| 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
| 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
| 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
| 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
| 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
| 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:
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
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg (100 Tablet Bottle)
NDC 65862-008-01
Metformin Hydrochloride Tablets, USP
500 mg
Rx only 100 Tablets
AUROBINDO
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg Bulk Tablet Label
4000 Tablets
BULK SHIPMENT
PLEASE HANDLE CAREFULLY
Rx only
Metformin Hydrochloride Tablets, USP 500 mg
Each tablet contains:
CAUTION:
Store at
Aurobindo Pharma Limited
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 850 mg (100 Tablet Bottle)
NDC 65862-009-01
Metformin Hydrochloride Tablets, USP
850 mg
Rx only 100 Tablets
AUROBINDO
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 850 mg Bulk Tablet Label
2500 Tablets
BULK SHIPMENT
PLEASE HANDLE CAREFULLY
Rx only
Metformin Hydrochloride Tablets, USP 850 mg
Each tablet contains:
CAUTION:
Store at
Aurobindo Pharma Limited
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 1000 mg (100 Tablet Bottle)
NDC 65862-010-01
Metformin Hydrochloride Tablets, USP
1000 mg
Rx only 100 Tablets
AUROBINDO
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 1000 mg Bulk Tablet Label
2000 Tablets
BULK SHIPMENT
PLEASE HANDLE CAREFULLY
Rx only
Metformin Hydrochloride Tablets, USP 1000 mg
Each tablet contains:
CAUTION:
Store at
Aurobindo Pharma Limited
Metformin HydrochlorideMetformin Hydrochloride TABLET, FILM COATED
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Metformin HydrochlorideMetformin Hydrochloride TABLET, FILM COATED
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Metformin HydrochlorideMetformin Hydrochloride TABLET, FILM COATED
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PLEASE, BE CAREFUL!
Be sure to consult your doctor before taking any medication!
