Metformin is used in the treatment of diabetes type 2, based on its FDA-labeled indications.
What is type 2 diabetes? Type 2 diabetes is a disease in which your blood glucose, or blood sugar , levels are too high. Glucose is your main source of energy. It comes from the foods you eat. A hormone called insulin helps the glucose get into your cells to give them energy. If … More on Diabetes Type 2 →
Lactic Acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride tablets; 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 hydrochloride tablets and by use of the minimum effective dose of metformin hydrochloride tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablet 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 hydrochloride tablets should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin hydrochloride tablets 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 hydrochloride tablets, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS .) Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride tablets; 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 µg/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 hydrochloride tablets and by use of the minimum effective dose of metformin hydrochloride tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablets 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 hydrochloride tablets should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin hydrochloride tablets 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
How Metformin is used
INDICATIONS AND USAGE Saxagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies ( 14 )]. Saxagliptin and metformin hydrochloride extended-release tablets are a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: • Not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.1 ) 1.1 Limitations of Use Saxagliptin and metformin hydrochloride extended-release tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
Dosage
DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride extended-release tablets or any other pharmacologic agent. Dosage of metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets in adults is 2,000 mg. Metformin hydrochloride extended-release tablets should generally be given once daily with the evening meal. Metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 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 hydrochloride extended-release tablets, 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 hydrochloride extended-release tablets may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.) Recommended Dosing Schedule Adults The usual starting dose of metformin hydrochloride extended-release tablets is 500 mg once daily with the evening meal. In general, clinically significant responses are not seen at doses below 1,500 mg per day. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2,000 mg once daily with the evening meal. The dosage of metformin hydrochloride extended-release tablets must be individualized on the basis of both effectiveness and tolerability. If glycemic control is not achieved on metformin hydrochloride extended-release tablets 2,000 mg once daily, a trial of metformin hydrochloride extended-release tablets 1,000 mg twice daily should be considered. If higher doses of metformin are required, metformin hydrochloride tablets should be used at total daily doses up to 2,550 mg administered in divided daily doses, as described above. (See CLINICAL PHARMACOLOGY: Clinical Studies . ) Patients receiving metformin hydrochloride tablets treatment may be safely switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily. Following a switch from metformin hydrochloride tablets to metformin hydrochloride extended-release tablets, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY: Clinical Studies ). Pediatrics Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established. Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter. Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride extended-release tablets if the patient's eGFR later falls below 30 mL/minute/1.73 m 2 (See WARNINGS and PRECAUTIONS ). Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride extended-release tablets 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 liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable. Concomitant Metformin Hydrochloride Extended-Release Tablets and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to 4 weeks of the maximum dose of metformin hydrochloride extended-release tablets monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin hydrochloride extended-release tablets 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 1 to 3 months of concomitant therapy with the maximum dose of metformin hydrochloride extended-release tablets and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride extended-release tablets. Concomitant Metformin Hydrochloride Extended-Release Tablets and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of metformin hydrochloride extended-release tablets therapy. Metformin hydrochloride extended-release tablets therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride extended-release tablets 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 2,000 mg for metformin hydrochloride extended-release tablets. 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 hydrochloride extended-release tablets. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations Metformin hydrochloride extended-release tablets are not recommended for use in pregnancy. Metformin hydrochloride extended-release tablets are not recommended in pediatric patients (below the age of 17 years). The initial and maintena
Warnings
WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning. ( 5.1 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually and vitamin B 12 at 2 year to 3 year intervals and manage any abnormalities. ( 5.2 ) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required. ( 5.3 ) 5.1 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. 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. Clinical recommendations based upon the patient’s renal function include [ see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ]: Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR). Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) ]. Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 mL/min/1.73 m 2 to 45 mL/min/1.73 m 2 . Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug interactions — The concomitant use of metformin hydrochloride extended-release tablets 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 [see Drug Interactions ( 7 )] . Consider more frequent monitoring of patients. 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. Assess renal function more frequently in elderly patients. 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. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 2 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal function is stable. 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 extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. 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). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended-release tablets. Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 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 or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 year to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [ see Adverse Reactions ( 6.1 ) ]. 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. 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 extended-release tablets [ see Drug Interactions ( 7 ) ]. 5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets
Drug interactions
DRUG INTERACTIONS Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 2: 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 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 glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7 ) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use ( 7 ) • Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake ( 7 ) Drug Interactions In Vivo Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC inf C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 Ratio of arithmetic means 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions (5.1) and Drug Interactions (7) . ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [ See Warnings and Precautions (5.1) and Drug Interactions (7) .] Topiramate 5 mg At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 5 mg metformin 1.25 1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC AUC = AUC inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 Ratio of arithmetic means, p-value of difference < 0.05 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10 AUC 0-24hr reported 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01
Side effects
ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Heart Failure [see Warnings and Precautions ( 5.3 )] Vitamin B 12 Concentrations [see Warnings and Precautions ( 5.4 )] Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.5 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Severe and disabling arthralgia [see Warnings and Precautions ( 5.7 )] Bullous pemphigoid [see Warnings and Precautions ( 5.8 )] • Most common adverse reactions with metformin HCl extended-release (incidence >5% and more often than placebo) are: diarrhea and nausea/vomiting. ( 6.1 ) • Most common adverse reactions with saxagliptin (incidence ≥5% and more often than placebo) are: upper respiratory tract infection, urinary tract infection, and headache. ( 6.1 ) • Adverse reactions with coadministered saxagliptin and metformin HCl (incidence ≥5% and more often than placebo) are: headache and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. Adverse Reactions in Placebo-Controlled Trials in Adults with Type 2 Diabetes Mellitus Metformin HCl In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of trial medication in 0.6% of the patients treated with metformin HCl extended-release. Saxagliptin The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies ( 14 )]. These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, 10.5% other races and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60mL/min/1.73m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin. Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin 5 mg N=882 Placebo N=799 Upper respiratory tract infection 7.7 7.6 Urinary tract infection 6.8 6.1 Headache 6.5 5.9 * The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin HCl, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin HCl, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Adverse Reactions with Concomitant Use with Insulin In the add-on to insulin trial [see Clinical Studies ( 14.1 )] , the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia [see Adverse Reactions ( 6.1 )]. Adverse Reactions Associated with Saxagliptin Coadministered with Metformin HCl Immediate-Release in Treatment-Naive Patients with Type 2 Diabetes Mellitus Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin HCl in treatment-naive patients. Table 2: Coadministration of Saxagliptin and Metformin HCl Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported in ≥5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin HCl Immediate-Release (and More Commonly than in Patients Treated with Metformin HCl Immediate-Release Alone) Number (%) of Patients Saxagliptin 5 mg + Metformin HCl* N=320 Placebo + Metformin HCl* N=328 Headache 24 (7.5) 17 (5.2) Nasopharyngitis 22 (6.9) 13 4.0) * Metformin HCl immediate-release was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2,000 mg daily. In patients treated with the combination of saxagliptin and metformin HCl immediate-release, either as saxagliptin add-on to metformin HCl immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence ≥5% in any treatment group in both trials. In the saxagliptin add-on to metformin HCl immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg + metformin HCl immediate-release group and 7.3% in the placebo + metformin HCl immediate-release group. Hypoglycemia In the saxagliptin clinical trials, adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible t
Based on its FDA-labeled indications, Metformin is used in the treatment of diabetes type 2. Use it only as prescribed — your clinician decides whether it's right for you.
What ICD-10 codes apply to Diabetes Type 2?
Diabetes Type 2 is coded in ICD-10-CM as E11.
Informational only, drawn from FDA labeling and NIH MedlinePlus — not medical advice. Talk to your clinician about whether Metformin is right for you.
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