Metformin Hydrochloride (50 brand names, 4 dosage forms, 1 route)
Available dosage forms: TABLET, EXTENDED RELEASE, TABLET, SOLUTION, FOR SUSPENSION, EXTENDED RELEASE.
Routes of administration: ORAL.
Brand Names
- ACTOPLUS MET
- ACTOPLUS MET XR
- ALOGLIPTIN; METFORMIN HYDROCHLORIDE
- AVANDAMET
- CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
- CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE
- DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
- EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
- EMPAGLIFLOZIN METFORMIN HYDROCHLORIDE
- EMPAGLIFLOZIN; LINAGLIPTIN; METFORMIN HYDROCHLORIDE
- EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE
- EMPAGLIFLOZIN;METFORMIN HYDROCHLORIDE
- FORTAMET
- GLIPIZIDE AND METFORMIN HYDROCHLORIDE
- GLUCOPHAGE
- GLUCOPHAGE XR
- GLUCOVANCE
- GLUMETZA
- GLYBURIDE AND METFORMIN HYDROCHLORIDE
- INVOKAMET …and 30 more
Boxed Warning
WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. 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. 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 Warnings and Precautions(5.1) ]. 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. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration(2.3), Contraindications(4), Warnings and Precautions (5.1) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt haemodialysis is recommended [see Warnings and Precautions(5.1) ].
Indications and Usage
Metformin Hydrochloride Extended-Release Tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Dosage and Administration
2.1 Adult Dosage Swallow Metformin Hydrochloride Extended-Release Tablets whole and never crush, cut or chew. The recommended starting dose of Metformin Hydrochloride Extended-Release Tablet is 500 mg orally once daily with the evening meal. Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved with Metformin Hydrochloride Extended-Release Tablet 2000 mg once daily, consider a trial of Metformin Hydrochloride Extended-Release Tablet 1000 mg twice daily. If higher doses are required, switch to Metformin Hydrochloride at total daily doses up to 2550 mg administered in divided daily doses, as described above. Patients receiving Metformin Hydrochloride Tablets may be switched to Metformin Hydrochloride Extended-Release Tablet once daily at the same total daily dose, up to 2000 mg once daily. 2.3 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of Metformin Hydrochloride Extended-Release Tablet and periodically thereafter. Metformin Hydrochloride Extended-Release Tablet is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2. Initiation of Metformin Hydrochloride Extended-Release Tablet in patients with an eGFR between 30 – 45 mL/minute/1.73 m 2is not recommended. In patients taking Metformin Hydrochloride Extended-Release Tablet whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit risk of continuing therapy. Discontinue Metformin Hydrochloride Extended-Release Tablet if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [see Warnings and Precautions (5.1) ] . 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue Metformin Hydrochloride Extended-Release Tablet 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 pati
Contraindications
Metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2) [see Warnings and Precautions (5.1)] . Hypersensitivity to metformin Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Warnings and Precautions
Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. 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. 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. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. 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 extended-release tablets. In metformin hydrochloride extended-release tablets, 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). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider. 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.
Adverse Reactions
The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [ see Boxed Warningand Warnings and Precautions (5.1)] Vitamin B 12Deficiency [see Warnings and Precautions (5.2)] Hypoglycemia [see Warnings and Precautions (5.3)] 6.1 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. Metformin Hydrochloride Extended-Release Tablets In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablet -than placebo-treated patients, are listed in Table 2. Table 2: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Extended-Release Tablets (n=781) Placebo (n=195) Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably esti
Drug Interactions
Table 3 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 3: Clinically Significant Drug Interactions with metformin hydrochloride extended-release tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance Clinical Impact: 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) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of
Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
Overdosage
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1) ].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.