Metformin

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# Black Box Warning

# Overview
Metformin is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include cobalamin deficiency, diarrhea, flatulence, indigestion, malabsorption syndrome, nausea, vomiting, asthenia, headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Metformin HCl Tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
- Dosing Information:
- There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent. Dosage of Metformin HCl, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age).
- Metformin HCl, USP should be given in divided doses with meals. Metformin HCl, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
- During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin HCl, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. 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 HCl, USP, either when used as monotherapy or in combination with sulfonylurea or insulin.
- Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.
- Short-term administration of Metformin HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
- Recommended Dosing Schedule
- Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.
- The usual starting dose of Metformin HCl Tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin HCl, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
- If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.
- Pediatrics - The usual starting dose of Metformin HCl, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.
- Transfer From Other Antidiabetic Therapy
- When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients
- If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
- With concomitant Metformin HCl, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Metformin HCl, USP 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin HCl, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin HCl, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)
- If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP.
Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients
- The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy. Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin HCl, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin HCl, USP. Further adjustment should be individualized based on glucose-lowering response.
Specific Patient Populations
- Metformin HCl, USP is not recommended for use in pregnancy. Metformin HCl, USP is not recommended in patients below the age of 10 years.
- The initial and maintenance dosing of Metformin HCl, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin HCl, USP.
- Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Metformin in adult patients.

### NonGuideline-Supported Use

### Hyperinsulinar obesity

### Polycystic ovary syndrome
- Dosing Information
- The recommended metformin dose for the treatment of women with polycystic ovary syndrome is 1500 to 2000 mg/day orally in divided doses (guideline dose).

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Type 2 diabetes mellitus(10 years or older, immediate-release tablet and solution; 17 years or older, extended-release tablets (Glucophage XR(R) and Fortamet(TM) only)
- Dosing Information
- Immediate Release
- The initial recommended dose of metformin for children, ages 10 to 16 years, is 500 mg twice daily, with meals. Dosage may be increased by 500 mg weekly, to a maximum of 2000 mg/day, in divided doses, if needed. Metformin is not recommended for children under 10 years of age.
- In adolescents 17 years or older with type 2 diabetes mellitus, the initial recommended dosage of metformin is 500 mg twice daily or 850 mg once daily given with meals. When using the 500-mg tablet, the dose may be increased at intervals of 1 week depending on the blood glucose response; whereas, with the 850-mg tablet, the dose should be increased at intervals of 2 weeks, up to a maximum of 2550 mg daily. Doses up to 2000 mg daily may be divided into 2 equal doses, but higher doses are tolerated better if they are divided into 3 doses.
- Extended-Release
- Glucophage XR(R):
- In adolescents 17 years or older with type 2 diabetes mellitus, the initial dose of metformin XR is 500 mg once daily with the evening meal. Dosage adjustments may be made weekly in increments of 500 mg to a maximum dose of 2000 mg daily. Patients who are receiving metformin may be switched to metformin XR at the same total daily dose, up to 2000 mg once daily. If metformin XR 2000 mg once daily does NOT achieve acceptable glycemic control, metformin XR 1000 mg twice daily may be tried.
- Fortamet(TM) Extended-Release:
- In adolescents 17 years or older, the initial dose of metformin extended-release (Fortamet(TM)) is 500 mg to 1000 mg once daily with the evening meal. Dosage adjustments may be made weekly in increments of 500 mg to a maximum of 2500 mg daily. Patients receiving immediate release metformin may be switched to extended release (Fortamet(TM)) once daily metformin at the same total daily dose.
- Oral Solution:
- The recommended initial dose of metformin oral solution in children 10 years or older is 500 mg orally twice daily. The dose may be titrated in 500 mg increments weekly to a maximum of 2000 mg/day in divided doses.
- Guideline Dosing:
- American Academy of Pediatrics guidelines recommend starting metformin at a dose 500 mg daily, with titration by 500 mg every 1 to 2 weeks to minimize gastrointestinal adverse effects. The ideal and maximum target dose is 2000 mg daily in divided doses. Extended-release metformin, dosed once in the evening, may be considered. Ideally, the target HbA1c in this patient population is less than 7%, but targets should be individualized to aid achievement with an ultimate goal of reaching the guideline target levels. In patients without hypoglycemic events and when otherwise appropriate, lower HbA1c targets may be considered.
- The safety and efficacy of metformin oral solution or immediate-release oral tablets have not been established in pediatric patients younger than 10 years.
- The safety and efficacy of extended-release Glumetza(TM) in pediatric patients, and Fortamet(TM) and Glucophage XR(R) in children younger than 17 years have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Metformin in pediatric patients.

### NonGuideline-Supported Use
- Hyperinsulinar obesity

# Contraindications
- Metformin HCl, USP is contraindicated in patients with:
- Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 1.5 mg/dL , 1.4 mg/dL  or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
- Known hypersensitivity to metformin HCl, USP.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
- Metformin HCl, USP 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.

# Warnings

### PRECAUTIONS
General
- Macrovascular OutcomesThere have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Metformin HCl or any other anti-diabetic drug.
- Monitoring of renal functionMetformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCl. In patients with advanced age, Metformin HCl should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those 80 years of age, renal function should be monitored regularly and, generally, Metformin HCl should not be titrated to the maximum dose.
- Before initiation of Metformin HCl therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin HCl discontinued if evidence of renal impairment is present.
- Use of concomitant medications that may affect renal function or metformin dispositionConcomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.
- 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)Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Metformin HCl should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
- Hypoxic statesCardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin HCl therapy, the drug should be promptly discontinued.
- Surgical procedures Metformin HCl therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
- Alcohol intakeAlcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCl.
- Impaired hepatic functionSince impaired hepatic function has been associated with some cases of lactic acidosis, Metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
- Vitamin B12 levelsIn controlled clinical trials of Metformin HCl of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin HCl or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin HCl and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).
- Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.
- Change in clinical status of patients with previously controlled type 2 diabetesA patient with type 2 diabetes previously well controlled on Metformin HCl who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Metformin HCl must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
- HypoglycemiaHypoglycemia does not occur in patients receiving Metformin HCl alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
- Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
- Loss of control of blood glucoseWhen a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin HCl and temporarily administer insulin. Metformin HCl may be reinstituted after the acute episode is resolved.
- The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin HCl or sulfonylurea monotherapy, combined therapy with Metformin HCl and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin HCl /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.
Laboratory Tests
- Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control.
- Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCl therapy, if this is suspected, Vitamin B12 deficiency should be excluded.

# Adverse Reactions

## Clinical Trials Experience
n a US double-blind clinical study of Metformin HCl in patients with type 2 diabetes, a total of 141 patients received Metformin HCl therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin HCl patients, and that were more common in Metformin HCl - than placebo-treated patients, are listed in Table 9.
- Reactions that were more common in Metformin HCl -than placebo-treated patients.
- Diarrhea led to discontinuation of study medication in 6% of patients treated with Metformin HCl. Additionally, the following adverse reactions were reported in  1.0 to  5.0% of Metformin HCl patients and were more commonly reported with Metformin HCl than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
Pediatric Patients
- In clinical trials with Metformin HCl in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

## Postmarketing Experience
There is limited information regarding Metformin Postmarketing Experience in the drug label.

# Drug Interactions
Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin HCl)
- GlyburideIn a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.
- FurosemideA single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with  metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
- NifedipineA single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
- Cationic drugsCationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Metformin HCl and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
- OtherCertain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Metformin HCl, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin HCl, the patient should be observed closely for hypoglycemia.
- In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.
- Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): B
- Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed.
- There are no adequate and well-controlled studies in pregnant women with Metformin HCl. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metformin in women who are pregnant.

### Labor and Delivery
- There is no FDA guidance on use of Metformin during labor and delivery.

### Nursing Mothers
- Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If Metformin HCl is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

### Pediatric Use
- The safety and effectiveness of Metformin HCl for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin HCl in this age group is supported by evidence from adequate and well-controlled studies of Metformin HCl in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults. A maximum daily dose of 2000 mg is recommended.

### Geriatic Use
- Controlled clinical studies of Metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin HCl should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Metformin HCl should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Metformin HCl.

### Gender
- There is no FDA guidance on the use of Metformin with respect to specific gender populations.

### Race
- There is no FDA guidance on the use of Metformin with respect to specific racial populations.

### Renal Impairment
- There is no FDA guidance on the use of Metformin in patients with renal impairment.

### Hepatic Impairment
- There is no FDA guidance on the use of Metformin in patients with hepatic impairment.

### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Metformin in women of reproductive potentials and males.

### Immunocompromised Patients
- There is no FDA guidance one the use of Metformin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin HCl, USP or any other pharmacologic agent. Dosage of Metformin HCl, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Metformin HCl, USP is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age).
- Metformin HCl, USP should be given in divided doses with meals. Metformin HCl, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
- During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin HCl, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. 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 HCl, USP, either when used as monotherapy or in combination with sulfonylurea or insulin.
- Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.
- Short-term administration of Metformin HCl, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Recommended Dosing Schedule
- Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.
- The usual starting dose of Metformin HCl Tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin HCl, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.
- If higher doses of metformin are required, Metformin HCl, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.
- Pediatrics - The usual starting dose of Metformin HCl, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.
Transfer From Other Antidiabetic Therapy
- When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin HCl, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin HCl, USP and Oral Sulfonylurea Therapy in Adult Patients
- If patients have not responded to four weeks of the maximum dose of Metformin HCl, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin HCl, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
- With concomitant Metformin HCl, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Metformin HCl, USP 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of Metformin HCl, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin HCl, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken.
- If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin HCl, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin HCl, USP.
Concomitant Metformin HCl, USP and Insulin Therapy in Adult Patients
- The current insulin dose should be continued upon initiation of Metformin HCl, USP therapy. Metformin HCl, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin HCl, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Metformin HCl, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin HCl, USP. Further adjustment should be individualized based on glucose-lowering response.
Specific Patient Populations
- Metformin HCl, USP is not recommended for use in pregnancy. Metformin HCl, USP is not recommended in patients below the age of 10 years.
- The initial and maintenance dosing of Metformin HCl, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin HCl, USP.
- Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)

### Monitoring
- Metformin HCl. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin HCl 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 HCl 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 HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
- Monitoring of renal functionMetformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCl. In patients with advanced age, Metformin HCl should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those 80 years of age, renal function should be monitored regularly and, generally, Metformin HCl should not be titrated to the maximum dose.
- Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control.
- Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with Metformin HCl therapy, if this is suspected, Vitamin B12 deficiency should be excluded.

# IV Compatibility
There is limited information regarding the compatibility of Metformin and IV administrations.

# Overdosage
- Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

# Pharmacology

## Mechanism of Action
- Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

## Structure
- Metformin Hydrochloride (HCl) Tablets, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin HCl, USP (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.
- The structural formula is as shown:
- Metformin HCl, USP is a white to off-white crystalline compound with a molecular formula of C4H11N5 - HCl and a molecular weight of 165.62. Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl, USP is 6.68.
- Metformin HCl Tablets, USP, contains 500 mg, 850 mg, or 1000 mg of metformin HCl, USP. Each tablet contains the inactive ingredients povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contain polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, gum acacia, maltodextrin, propylene glycol and natural flavors.

## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Metformin in the drug label.

## Pharmacokinetics
Absorption and Bioavailability
- The absolute bioavailability of a Metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of Metformin HCl 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
- The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin HCl 850 mg averaged 654  358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Metformin HCl, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of Metformin HCl, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism and Elimination
- Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations
Patients with Type 2 Diabetes
- In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.
Renal Insufficiency
- In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS).
Hepatic Insufficiency
- No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
Geriatrics
- Limited data from controlled pharmacokinetic studies of Metformin HCl 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 (see Table 1). Metformin HCl Tablets treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Pediatrics
- After administration of a single oral Metformin HCl 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 HCl 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 HCl 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
- In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose  of approximately 240 mg/dL), treatment with Metformin HCl (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).
- A 29-week, double-blind, placebo-controlled study of Metformin HCl and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with Metformin HCl 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of Metformin HCl increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed Metformin HCl 2500 mg. Patients in the Metformin HCl only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking Metformin HCl 2000 mg/glyburide 20 mg or Metformin HCl 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to Metformin HCl (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of Metformin HCl and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were 77 mg/dL,  68 mg/dL, and 1.9%, respectively (see Table 3).
- The magnitude of the decline in fasting blood glucose concentration following the institution of - Metformin HCl Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.
- In clinical studies, Metformin HCl, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4).
- In contrast to sulfonylureas, body weight of individuals on Metformin HCl tended to remain stable or even decrease somewhat (see Tables 2 and 3).
- A 24-week, double-blind, placebo-controlled study of Metformin HCl plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive Metformin HCl plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, Metformin HCl plus insulin versus insulin plus placebo, respectively, p=0.04.
- A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46  0.97%, the addition of Metformin HCl maintained similar glycemic control (HbA1c 7.15  0.61 versus 6.97  0.62 for Metformin HCl plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68  30.22 versus an increase of 0.43  25.20 units for Metformin HCl plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of Metformin HCl plus insulin resulted in reduction in body weight of 3.11  4.30 lbs, compared to an increase of 1.30  6.08 lbs for placebo plus insulin, p=0.01.
Pediatric Clinical Studies
- In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with Metformin HCl (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 8).

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively.
- These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
- There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
- Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

# Clinical Studies
There is limited information regarding Clinical Studies of Metformin in the drug label.

# How Supplied
- Metformin HCl Tablets, USP 500 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed IP 218 on obverse and 500 on the reverse.
- They are available as follows:
- Bottles of 100: NDC 65162-218-10
- Bottles of 500: NDC 65162-218-50
- Bottles of 1000: NDC 65162-218-11
- Metformin HCl Tablets, USP 850 mg are blackberry flavored, white to off-white, round, biconvex, film-coated tablets debossed IP 219 on obverse and 850 on the reverse.
- They are available as follows:
- Bottles of 100: NDC 65162-219-10
- Bottles of 500: NDC 65162-219-50
- Bottles of 1000: NDC 65162-219-11
- Metformin HCl Tablets, USP 1000 mg are blackberry flavored, white to off-white, oval, biconvex, bisected, film-coated tablets debossed IP 220 on obverse and 1000 on the reverse.
- They are available as follows:
- Bottles of 100: NDC 65162-220-10
- Bottles of 500: NDC 65162-220-50
- Bottles of 1000: NDC 65162-220-11

## Storage
- Store at 20 to 25 C (68 to 77 F); excursions permitted to 15 to 30 C (59 to 86 F) 

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients should be informed of the potential risks and benefits of Metformin HCl and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
- The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Metformin HCl immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin HCl, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
- Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Metformin HCl.
- Metformin HCl alone does not usually cause hypoglycemia, although it may occur when Metformin HCl is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)

# Precautions with Alcohol
- Alcohol intakeAlcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCl.

# Brand Names
Fortamet,
Glucophage,
Glucophage XR,
Riomet,
Glumetza.

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price