Metformin Hydrochloride

REMEDYREPACK INC.

Metformin Hydrochloride Tablets, USP

FULL PRESCRIBING INFORMATION: CONTENTS*

• Description Section
• Clinical Pharmacology Section
• Indications & Usage Section
• Contraindications Section
• Warnings Section
• Precautions Section
• Side Effects Section
• Overdosage Section
• Dosage & Administration Section
• How Supplied Section
• SPL Patient Package Insert Section
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

FULL PRESCRIBING INFORMATION

Description Section

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Clinical Pharmacology Section

PRECAUTIONS

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Table 1

Table 1

Table 1 WARNINGS

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Table 6

Indications & Usage Section

Contraindications Section

• 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 Section

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 Section

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 levels_12 121212 PRECAUTIONS: Laboratory Tests

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

Hypoglycemia



Loss of control of blood glucose—

WARNINGS PRECAUTIONS



Patient Information

DOSAGE AND ADMINISTRATION

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

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Cationic drugs—

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

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

Side Effects Section

Table 7

Overdosage Section

WARNINGS

Dosage & Administration Section

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.

Adults -



Pediatrics –

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WARNINGS

How Supplied Section

500 mg Tablets:










850 mg Tablets:










1000 mg Tablets:










Storage

SPL Patient Package Insert Section

Rx only

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?”)

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

• 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.

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

Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited

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