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Metformin Hydrochloride

REMEDYREPACK INC.


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

BOXED WARNING

WARNINGS

Lactic Acidosis:
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 tablets or metformin hydrochloride extended-release tablets and by use of the minimum effective dose of metformin hydrochloride tablets or metformin hydrochloride extended-release tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablets or metformin hydrochloride extended-release tablets treatment should not be initiated in patients80 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 tablets and 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 tablets and 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 tablets or metformin hydrochloride extended-release tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride tablets and metformin hydrochloride extended-release tablets should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see alsoPRECAUTIONS).
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 alsoPRECAUTIONS). Metformin hydrochloride tablets and 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 tablets or 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 tablets or 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 alsoPRECAUTIONS.)
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 tablets or 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 alsoCONTRAINDICATIONSandPRECAUTIONS.)

METFORMIN HYDROCHLORIDE DESCRIPTION



Metformin Hydrochloride







System Components and Performance


CLINICAL PHARMACOLOGY

Mechanism of Action
PRECAUTIONS

PHARMACOKINETICS

Absorption and Bioavailability





Distribution



Metabolism and Elimination
Table 1

USE IN SPECIFIC POPULATIONS

Patients with Type 2 Diabetes
Table 1


Renal Insufficiency
Table 1WARNINGS).

Hepatic Insufficiency
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Geriatrics
Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is 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 (seeTable 1). Metformin hydrochloride and metformin hydrochloride extended-release treatment should not be initiated in patients80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. (SeeWARNINGSandDOSAGE AND ADMINISTRATION.)

Table 1. Select Mean (Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin
a -All doses given fasting except the first 18 doses of the multiple dose studiesb -Peak plasma concentrationc -Time to peak plasma concentrationd -Combined results (average means) of five studies: mean age 32 years (range 23-59 years)e -Kinetic study done following dose 19, given fastingf -Elderly subjects, mean age 71 years (range 65-81 years)g -CLcr = creatinine clearance normalized to body surface area of 1.73 m2Subject Groups: Metformin dose(number of subjects)Cmaxb (Tmaxc (hrs)Renal Clearance (mL/min)Healthy, nondiabetic adults:500 mg single dose (24)1.03 (2.75 (600 (850 mg single dose (74)d1.60 (2.64 (552 (850 mg three times daily for 19 dosese (9)2.01 (1.79 (642 (Adults with type 2 diabetes:850 mg single dose (23)1.48 (3.32 (491 (850 mg three times daily for 19 dosese (9)1.90 (2.01 (550 (Elderlyf, healthy nondiabetic adults:850 mg single dose (12)2.45 (2.71 (412 (98)Renal-impaired adults:850 mg single doseMild (CLcrg 61-90 mL/min) (5)1.86 (3.20 (384 (Moderate (CLcr 31-60 mL/min) (4)4.12 (3.75 (108 (57)Severe (CLcr 10-30 mL/min) (6)3.93 (4.01 (130 (90)
Pediatrics
After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 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
Table 2


Table 3Table 3



Table 4


Tables 23
Table 5




METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS

Table 6


DOSAGE AND ADMINISTRATION
Table 7


DOSAGE AND ADMINISTRATION
Table 8


Table 9



Pediatric Clinical Studies
Table 10





INDICATIONS & USAGE




METFORMIN HYDROCHLORIDE CONTRAINDICATIONS


WARNINGSPRECAUTIONS


PRECAUTIONS

WARNINGS

Lactic Acidosis:
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 tablets or metformin hydrochloride extended-release tablets and by use of the minimum effective dose of metformin hydrochloride tablets or metformin hydrochloride extended-release tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablets or metformin hydrochloride extended-release tablets treatment should not be initiated in patients80 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 tablets and 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 tablets and 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 tablets or metformin hydrochloride extended-release tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride tablets and metformin hydrochloride extended-release tablets should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see alsoPRECAUTIONS).
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 alsoPRECAUTIONS). Metformin hydrochloride tablets and 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 tablets or 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 tablets or 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 alsoPRECAUTIONS.)
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 tablets or 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 alsoCONTRAINDICATIONSandPRECAUTIONS.)

PRECAUTIONS

General

WARNINGSDOSAGE AND ADMINISTRATION


PRECAUTIONS: Drug Interactions

CONTRAINDICATIONS









PRECAUTIONS: Laboratory Tests


WARNINGS






INFORMATION FOR PATIENTS


WARNINGSPRECAUTIONS




LABORATORY TESTS

DOSAGE AND ADMINISTRATION


DRUG INTERACTIONS

(clinical evaluation of drug interactions done with metformin hydrochloride tablets)

DOSAGE AND ADMINISTRATION:Concomitant Metformin Hydrochloride Tablets or Metformin Hydrochloride Extended-release Tablets and Oral Sulfonylurea Therapy











CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY





PREGNANCY

Teratogenic Effects: Pregnancy Category B.



NURSING MOTHERS



PEDIATRIC USE

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


GERIATRIC USE

CONTRAINDICATIONSWARNINGSCLINICAL PHARMACOLOGY: PharmacokineticsWARNINGSDOSAGE AND ADMINISTRATION

METFORMIN HYDROCHLORIDE ADVERSE REACTIONS

Table 11



Table 12




Pediatric Patients


OVERDOSAGE

WARNINGS

DOSAGE & ADMINISTRATION


Recommended Dosing Schedule





Recommended Dosing Schedule



CLINICAL PHARMACOLOGY, Clinical Studies
CLINICAL PHARMACOLOGY, Clinical Studies



Transfer from Other Antidiabetic Therapy


Concomitant Metformin Hydrochloride Tablets or Metformin Hydrochloride Extended-release Tablets and Oral Sulfonylurea Therapy in Adult Patients




Concomitant Metformin Hydrochloride Tablets or Metformin Hydrochloride Extended-release Tablets and Insulin Therapy in Adult Patients


Specific Patient Populations

WARNINGS

HOW SUPPLIED
























STORAGE AND HANDLING




PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION














Metformin Hydrochloride

Metformin Hydrochloride

Metformin Hydrochloride

Metformin Hydrochloride TABLET, EXTENDED RELEASE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:49349-707(NDC:62037-571)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
METFORMIN HYDROCHLORIDE METFORMIN 500 mg

Inactive Ingredients

Ingredient Name Strength
HYPROMELLOSE 2208 (3 MPA.S)
SILICON DIOXIDE
MAGNESIUM STEARATE

Product Characteristics

Color Size Imprint Code Shape
white 20 mm 571;500 OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:49349-707-02 30 in 1 BLISTER PACK

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA075979 2011-09-08


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