Metformin Hydrochloride
Metformin Hydrochloride Extended-Release 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
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg (100 Tablet Bottle)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 750 mg (100 Tablet Bottle)
FULL PRESCRIBING INFORMATION
METFORMIN HYDROCHLORIDE DESCRIPTION
N,N
4115a
System Components and Performance -
CLINICAL PHARMACOLOGY
Mechanism of Action
PRECAUTIONS
Pharmacokinetics
max
max
max
maxmax
Table 1
Special Populations
Table 1
Table 1 WARNINGS
max Table 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)
|
1.03 (±0.33)
|
2.75 (±0.81)
|
600 (±132)
|
| 850 mg single dose (74)d
|
1.6 (±0.38) |
2.64 (±0.82) |
552 (±139) |
| 850 mg three times daily for 19 dosese (9) |
2.01 (±0.42) |
1.79 (±0.94) |
642 (±173) |
|
Adults with type 2 diabetes:
|
|||
| 850 mg single dose (23)
|
1.48 (±0.5) |
3.32 (±1.08) |
491 (±138) |
| 850 mg three times daily for 19 dosese (9) |
1.9 (±0.62) |
2.01 (±1.22) |
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 61-90 mL/min) (5)
|
1.86 (±0.52) |
3.2 (±0.45) |
384 (±122) |
|
Moderate (CLcr 31-60 mL/min) (4)
|
4.12 (±1.83) |
3.75 (±0.5) |
108 (±57) |
|
Severe (CLcr 10-30 mL/min) (6) |
3.93 (±0.92) |
4.01 (±1.1) |
130 (±90) |
max
Clinical Studies
1c1c1c1c1c1c1c
1cTable 2
| Metformin Hydrochloride Extended-Release Tablets | Placebo | |||||
|---|---|---|---|---|---|---|
| 500 mg Once Daily |
1000 mg Once Daily |
1500 mg Once Daily |
2000 mg Once Daily |
1000 mg Twice Daily |
||
|
* All patients on diet therapy at Baseline a All comparisons versus Placebo ** Not statistically significant |
||||||
|
Hemoglobin A1c (%)
|
(n=115)
|
(n=115)
|
(n=111)
|
(n=125)
|
(n=112)
|
(n=111)
|
| Baseline |
8.2 |
8.4 |
8.3 |
8.4 |
8.4 |
8.4 |
| Change at FINAL VISIT |
-0.4 |
-0.6 |
-0.9 |
-0.8 |
-1.1 |
0.1 |
| p-valuea
|
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
- |
|
FPG (mg/dL)
|
(n=126)
|
(n=118)
|
(n=120)
|
(n=132)
|
(n=122)
|
(n=113)
|
| Baseline |
182.7 |
183.7 |
178.9 |
181 |
181.6 |
179.6 |
| Change at FINAL VISIT |
-15.2 |
-19.3 |
-28.5 |
-29.9 |
-33.6 |
7.6 |
| p-valuea
|
<0.001 |
<0.001 |
<0.001 |
<0.001 |
<0.001 |
- |
|
Body Weight (lbs)
|
(n=125)
|
(n=119)
|
(n=117)
|
(n=131)
|
(n=119)
|
(n=113)
|
| Baseline
|
192.9
|
191.8
|
188.3
|
195.4
|
192.5
|
194.3
|
| Change at FINAL VISIT |
-1.3 |
-1.3 |
-0.7 |
-1.5 |
-2.2 |
-1.8 |
| p-valuea
|
NS** |
NS** |
NS** |
NS** |
NS** |
- |
1cTable 3
| Metformin Hydrochloride Tablets 500 mg Twice Daily |
Metformin Hydrochloride Extended- Release Tablets |
||
|---|---|---|---|
| 1000 mg Once Daily |
1500 mg Once Daily |
||
|
* All patients on metformin hydrochloride tablets 500 mg twice daily at Baseline a n=68 |
|||
|
Hemoglobin A1c (%)
|
(n=67)
|
(n=72)
|
(n=66)
|
| Baseline |
7.06 |
6.99 |
7.02 |
| Change at 12 Weeks |
0.14 |
0.23 |
0.04 |
| (95% CI) |
(-0.03, 0.31) |
(0.1, 0.36) |
(-0.08, 0.15) |
| Change at FINAL VISIT |
0.14a
|
0.27 |
0.13 |
| (95% CI) |
(-0.04, 0.31) |
(0.11, 0.43) |
(-0.02, 0.28) |
|
FPG (mg/dL)
|
(n=69)
|
(n=72)
|
(n=70)
|
| Baseline |
127.2 |
131 |
131.4 |
| Change at 12 Weeks |
12.9 |
9.5 |
3.7 |
| (95% CI) |
(6.5, 19.4) |
(4.4, 14.6) |
(-0.4, 7.8) |
| Change at FINAL VISIT |
14 |
11.5 |
7.6 |
| (95% CI) |
(7, 21) |
(4.4, 18.6) |
(1, 14.2) |
|
Body Weight (lbs)
|
(n=71)
|
(n=74)
|
(n=71)
|
| Baseline |
210.3 |
202.8 |
192.7 |
| Change at 12 Weeks |
0.4 |
0.9 |
0.7 |
| (95% CI) |
(-0.4, 1.5) |
(0, 2) |
(-0.4, 1.8) |
| Change at FINAL VISIT |
0.9 |
1.1 |
0.9 |
| (95% CI) |
(-0.4, 2.2) |
(-0.2, 2.4) |
(-0.4, 2) |
Table 4
| Metformin Hydrochloride Extended-Release Tablets | Placebo | |||||
|---|---|---|---|---|---|---|
| 500 mg Once Daily |
1000 mg Once Daily |
1500 mg Once Daily |
2000 mg Once Daily |
1000 mg Twice Daily |
||
|
*All patients on diet therapy at Baseline |
||||||
|
Total Cholesterol (mg/dL)
|
(n=120)
|
(n=113)
|
(n=110)
|
(n=126)
|
(n=117)
|
(n=110)
|
| Baseline
|
210.3
|
218.1
|
214.6
|
204.4
|
208.2
|
208.6
|
| Mean % Change at FINAL VISIT |
1%
|
1.7%
|
0.7%
|
-1.6%
|
-2.6%
|
2.6%
|
|
Total Triglycerides (mg/dL)
|
(n=120)
|
(n=113)
|
(n=110)
|
(n=126)
|
(n=117)
|
(n=110)
|
| Baseline
|
220.2
|
211.9
|
198
|
194.2
|
179
|
211.7
|
| Mean % Change at FINAL VISIT
|
14.5%
|
9.4%
|
15.1%
|
14.9%
|
9.4%
|
10.9%
|
|
LDL-Cholesterol (mg/dL)
|
(n=119)
|
(n=113)
|
(n=109)
|
(n=126)
|
(n=117)
|
(n=107)
|
| Baseline
|
131
|
134.9
|
135.8
|
125.8
|
131.4
|
131.9
|
| Mean % Change at FINAL VISIT
|
-1.4%
|
-1.6%
|
-3.5%
|
-3.3%
|
-5.5%
|
3.2%
|
|
HDL-Cholesterol (mg/dL)
|
(n=120)
|
(n=108)
|
(n=108)
|
(n=125)
|
(n=117)
|
(n=108)
|
| Baseline |
40.8 |
41.6 |
40.6 |
40.2 |
42.4 |
39.4 |
| Mean % Change at FINAL VISIT |
6.2% |
8.6% |
5.5% |
6.1% |
7.1% |
5.8% |
Table 5
| Metformin Hydrochloride Extended- Release Tablets | ||
|---|---|---|
| 1000 mg Once Daily |
1500 mg Once Daily |
|
|
Total Cholesterol (mg/dL)
|
(n=70)
|
(n=66)
|
| Baseline |
201.9 |
201.6 |
| Mean % Change at FINAL VISIT |
1.3% |
0.1% |
|
Total Triglycerides (mg/dL)
|
(n=70)
|
(n=66)
|
| Baseline |
169.2 |
206.8 |
| Mean % Change at FINAL VISIT |
25.3% |
33.4% |
|
LDL-Cholesterol (mg/dL)
|
(n=70)
|
(n=66)
|
| Baseline |
126.2 |
115.7 |
| Mean % Change at FINAL VISIT |
-3.3% |
-3.7% |
|
HDL-Cholesterol (mg/dL)
|
(n=70)
|
(n=65)
|
| Baseline |
41.7 |
44.6 |
| Mean % Change at FINAL VISIT |
1% |
-2.1% |
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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets; 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 hydrochloride extended-release tablets and by use of the minimum effective dose of metformin hydrochloride extended-release tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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 extended-release tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride extended-release tablets 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 extended-release 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 hydrochloride extended-release tablets, 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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets, 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
WARNINGS DOSAGE AND ADMINISTRATION
PRECAUTIONS: Drug Interactions
CONTRAINDICATIONS
12
1212 1212 PRECAUTIONS: Laboratory Tests
121212
WARNINGS
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)
max DOSAGE AND ADMINISTRATION: Concomitant Metformin Hydrochloride Extended-Release Tablets and Oral Sulfonylurea Therapy in Adult Patients
maxmax
maxmax
Carcinogenesis, Mutagenesis, Impairment of Fertility
in vitroS. typhimuriumin vivo
Pregnancy
Teratogenic effects
Pregnancy Category B
Nursing Mothers
Pediatric Use
Geriatric Use
CONTRAINDICATIONS, WARNINGS, CLINICAL PHARMACOLOGY: Pharmacokinetics WARNINGS DOSAGE AND ADMINISTRATION
METFORMIN HYDROCHLORIDE ADVERSE REACTIONS
Table 6
| Metformin Hydrochloride extended-release tablets (n=781) |
Placebo (n=195) |
|
|---|---|---|
| Adverse Reaction | % of Patients | |
|
*Reactions that were more common in metformin hydrochloride extended-release tablets- than placebo-treated patients. |
||
| Diarrhea |
9.6 |
2.6 |
| Nausea/Vomiting |
6.5 |
1.5 |
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 hydrochloride extended-release tablets, either when used as monotherapy or in combination with sulfonylurea or insulin.
Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Patient Information
Recommended Dosing Schedule
CLINICAL PHARMACOLOGY: Clinical Studies
CLINICAL PHARMACOLOGY: Clinical Studies
Concomitant Metformin Hydrochloride Extended-Release Tablets and Oral Sulfonylurea Therapy in Adult Patients
Concomitant Metformin Hydrochloride Extended-Release Tablets and Insulin Therapy in Adult Patients
Specific Patient Populations
WARNINGS
HOW SUPPLIED
Metformin Hydrochloride Extended-Release Tablets USP, 500 mg
Metformin Hydrochloride Extended-Release Tablets USP, 750 mg
Store at
Aurobindo Pharma USA, Inc.
Aurobindo Pharma Limited
Patient Information
Metformin Hydrochloride Extended-Release Tablets, USP
Rx only
What are metformin hydrochloride extended-release tablets?
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 hydrochloride extended-release tablets (See “What are the side effects of metformin hydrochloride extended-release tablets?”)
Who should not take metformin hydrochloride extended-release tablets?
Do not take metformin hydrochloride extended-release tablets 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 extended-release tablets be used in children?
How should I take metformin hydrochloride extended-release 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 hydrochloride extended-release tablets 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 extended-release tablets for a short time.
- start to take other medicines or change how you take a medicine. Metformin hydrochloride extended-release tablets can affect how well other drugs work, and some drugs can affect how well metformin hydrochloride extended-release tablets work. Some medicines may cause high blood sugar.
Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed
What should I avoid while taking metformin hydrochloride extended-release tablets?
What are the side effects of metformin hydrochloride extended-release tablets?
Lactic Acidosis . In rare cases, metformin hydrochloride extended-release tablets can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This build-up can cause serious damage.
stop using metformin hydrochloride extended-release tablets 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 65862-291-01
Metformin Hydrochloride
Extended-Release Tablets, USP
500 mg
PHARMACIST: Please dispense with patient
information leaflet provided separately.
Rx only 100 Tablets
AUROBINDO
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 750 mg (100 Tablet Bottle)
NDC 65862-292-01
Metformin Hydrochloride
Extended-Release Tablets, USP
750 mg
PHARMACIST: Please dispense with patient
information leaflet provided separately.
Rx only 100 Tablets
AUROBINDO
Metformin HydrochlorideMetformin Hydrochloride TABLET, EXTENDED RELEASE
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Metformin HydrochlorideMetformin Hydrochloride TABLET, EXTENDED RELEASE
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PLEASE, BE CAREFUL!
Be sure to consult your doctor before taking any medication!
