19 August 2019From the archive
Metformin hydrochloride
label of 3 May 201819 August 2019published 19 August 2019, reconstructed from the DailyMed archive
Approved uses
1 entry reworded without a change of meaning.
Dosage and administration
Added in this revision
- Added: Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses.
- Added: Pediatric Dosage for Metformin Hydrochloride Tablets The recommended starting dose of metformin hydrochloride tablets for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals.
- Added: Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily.
Removed in this revision
- Removed: There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin or any other pharmacologic agent.
- Removed: Dosage of metformin must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses.
- Removed: The maximum recommended daily dose of metformin hydrochloride tablets is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age).
- Removed: Metformin hydrochloride tablets should be given in divided doses with meals and should be started at a low dose, with gradual dose escalation, to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
- Removed: During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin and identify the minimum effective dose for the patient.
- Removed: Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months.
- Removed: 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.
- Removed: 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.
- Removed: Short-term administration of metformin may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
- Removed: In general, clinically significant responses are not seen at doses below 1500 mg per day.
- Removed: 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.
- Removed: The dosage of metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerability.
- Removed: Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks.
- Removed: For those patients requiring additional glycemic control, metformin hydrochloride tablets may be given to a maximum daily dose of 2550 mg per day.
- Removed: Pediatrics The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day, given with meals.
- Removed: Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.
- Removed: The dosage of metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerability.
- Removed: Concomitant Metformin and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to 4 weeks of the maximum dose of metformin monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred.
- Removed: Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
- Removed: With concomitant metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.
- Removed: In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin hydrochloride tablets 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of metformin hydrochloride tablets and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA 1c, and plasma glucose response (see CLINICAL PHARMACOLOGY: Clinical Studies).
- Removed: However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal.
- Removed: With concomitant metformin and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased.
- Removed: Appropriate precautions should be taken.
- Removed: (See Package Insert of the respective sulfonylurea.) If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of metformin and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin.
- Removed: Concomitant Metformin and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of metformin therapy.
- Removed: Metformin therapy should be initiated at 500 mg once daily in patients on insulin therapy.
- Removed: For patients not responding adequately, the dose of metformin should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved.
- Removed: The maximum recommended daily dose is 2500 mg for metformin hydrochloride tablets.
- Removed: 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.
- Removed: Further adjustment should be individualized based on glucose-lowering response.
- Removed: Specific Patient Populations Metformin is not recommended for use in pregnancy.
- Removed: Metformin hydrochloride tablets are not recommended in patients below the age of 10 years.
- Removed: The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population.
- Removed: Any dosage adjustment should be based on a careful assessment of renal function.
3 entries reworded without a change of meaning.
Forms and strengths
Added in this revision
- Added: Metformin Hydrochloride Tablets USP, 500 mg: White, biconvex, circular shaped film coated tablets with 'A' debossed on one side and '12' debossed on the other side.
- Added: Metformin Hydrochloride Tablets USP, 850 mg: White, biconvex, circular shaped film coated tablets with 'A' debossed on one side and '13' debossed on the other side.
- Added: Metformin Hydrochloride Tablets USP, 1000 mg: White, biconvex, oval shaped film coated tablets with a score line in between '1' and '4' on one side and 'A' debossed on the other side.
Contraindications
Added in this revision
- Added: Hypersensitivity to metformin.
Removed in this revision
- Removed: Known hypersensitivity to metformin hydrochloride.
- Removed: Diabetic ketoacidosis should be treated with insulin.
1 entry reworded without a change of meaning.
Warnings and precautions
Added in this revision
- Added: Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.
- Added: These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
- Added: Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL.
- Added: Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
- Added: If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride.
- Added: In metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions).
- Added: Hemodialysis has often resulted in reversal of symptoms and recovery.
- Added: Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride and report these symptoms to their healthcare provider.
- Added: For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal impairment -The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.
- Added: The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.
- Added: Clinical recommendations based upon the patient's renal function include: Before initiating metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR).
- Added: Metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2.
- Added: Initiation of metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2.
- Added: Obtain an eGFR at least annually in all patients taking metformin hydrochloride.
- Added: In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
- Added: In patients taking metformin hydrochloride whose eGFR falls below 45 mL/min/1.73 m 2, assess the benefit and risk of continuing therapy.
- Added: Drug interactions - The concomitant use of metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.
- Added: Consider more frequent monitoring of patients.
- Added: Age 65 or greater - The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.
- Added: Assess renal function more frequently in elderly patients.
- Added: Radiologic studies with contrast - Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis.
- Added: Stop metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
- Added: Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride if renal function is stable.
- Added: Surgery and other procedures - Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.
- Added: Hypoxic states - Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
- Added: Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia.
- Added: When such an event occurs, discontinue metformin hydrochloride.
- Added: Excessive alcohol intake - Alcohol potentiates the effect of metformin on lactate metabolism.
- Added: Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride.
- Added: Hepatic impairment - Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis.
- Added: This may be due to impaired lactate clearance resulting in higher lactate blood levels.
- Added: Therefore, avoid use of metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.
- Added: Vitamin B 12 Deficiency In Metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
- Added: Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride or vitamin B 12 supplementation.
- Added: Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels.
- Added: Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on metformin hydrochloride and manage any abnormalities.
- Added: Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia.
- Added: Metformin hydrochloride may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue.
- Added: Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride.
- Added: Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride.
Warnings
Removed in this revision
- Removed: WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.
- Removed: The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
- Removed: Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see PRECAUTIONS).
- Removed: Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
- Removed: Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and PRECAUTIONS).
- Removed: If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride tablets and institute general supportive measures in a hospital setting.
- Removed: Prompt hemodialysis is recommended (see PRECAUTIONS).
Adverse reactions
Added in this revision
- Added: The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis Vitamin B 12 Deficiency Hypoglycemia Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Added: In a U.S. clinical trial of metformin hydrochloride in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride up to 2550 mg per day.
- Added: Table 1: Adverse Reactions from a Clinical Trial of Metformin Hydrochloride Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Diarrhea led to discontinuation of metformin hydrochloride in 6% of patients.
- Added: In metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
- Added: Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin.
- Added: Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Removed in this revision
- Removed: In a U.S. double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablets therapy (up to 2550 mg per day) and 145 patients received placebo.
- Removed: Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets.
3 entries reworded without a change of meaning.
Drug interactions
Added in this revision
- Added: Table 3 presents clinically significant drug interactions with metformin hydrochloride.
Removed in this revision
- Removed: Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin Hydrochloride Tablets) Glyburide- In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.
- Removed: Decreases in glyburide AUC and C max were observed, but were highly variable.
- Removed: 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 (see DOSAGE AND ADMINISTRATION: Concomitant Metformin and Oral Sulfonylurea Therapy in Adult Patients).
- Removed: Furosemide- A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration.
- Removed: Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.
- Removed: When administered with metformin, the C max 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.
- Removed: No information is available about the interaction of metformin and furosemide when coadministered chronically.
- Removed: Nifedipine- A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine.
- Removed: T max and half-life were unaffected.
- Removed: Nifedipine appears to enhance the absorption of metformin.
- Removed: Metformin had minimal effects on nifedipine.
- Removed: Drugs that reduce metformin clearance- Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.
- Removed: Consider the benefits and risks of concomitant use.
- Removed: 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.
- Removed: There was no change in elimination half-life in the single-dose study.
- Removed: Metformin had no effect on cimetidine pharmacokinetics.
- Removed: In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.
- Removed: 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.
- Removed: Other- Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
- Removed: 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.
- Removed: When such drugs are administered to a patient receiving metformin hydrochloride tablets, the patient should be closely observed for loss of blood glucose control.
- Removed: When such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, the patient should be observed closely for hypoglycemia.
- Removed: Carbonic anhydrase inhibitors- Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
- Removed: Concomitant use of these drugs with metformin hydrochloride tablets may increase the risk for lactic acidosis.
- Removed: Consider more frequent monitoring of these patients.
- Removed: Alcohol- Alcohol is known to potentiate the effect of metformin on lactate metabolism.
- Removed: Warn patients against excessive alcohol intake while receiving metformin hydrochloride tablets.