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Biguanides

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Diabetes:  Drug Class Navigation  top of page

Secretagogues

Insulin sensitizers

Alpha-glucosidase inh

Sulfonylureas Biguanides e.g. Metformin   Alpha-glucosidase Inhibitors
 Meglitinides (e.g. Prandin) Glitazones - Thiazolidinediones  

Peptide analogs

AMYLIN AGONISTS - Anti-hyperglycemic Synthetic Analogs DPP-4 INHIBITORS -  Dipeptidyl peptidase-4 inhibitor  –    Gliptins Glucagon-like peptide-1 (GLP-1) AGONIST - Incretin Mimetics

Drug Monographs   top of page

Products

metformin (Glucophage ®) Avandamet® (Rosiglitazone + Metformin)
Glucovance (Glyburide + Metformin) INVOKAMET ® (canagliflozin and metformin hydrochloride) tablets
Metaglip (Glipizide + Metformin) XIGDUO XR ® (dapagliflozin and metformin HCl extended-release) tablets

Typical reductions in A1C values - Biguanides:

 

1.5 - 2.0%.
Background

WARNINGS:

WARNING
Lactic Acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOPHAGE or GLUCOPHAGE XR; 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 GLUCOPHAGE or GLUCOPHAGE XR and by use of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOPHAGE or GLUCOPHAGE XR treatment should not be initiated in patients geq80 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, GLUCOPHAGE and GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS - PACKAGE INSERT).

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 - PACKAGE INSERT). GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, 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 GLUCOPHAGE or GLUCOPHAGE XR 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 - PACKAGE INSERT)

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 GLUCOPHAGE or GLUCOPHAGE XR, 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 - PACKAGE INSERT)

metformin (Glucophage ®):   top of page

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 package insert for 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


INDICATIONS AND USAGE
GLUCOPHAGE (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


CONTRAINDICATIONS
GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels geq1.5 mg/dL [males],
geq1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see package insert for WARNINGS and PRECAUTIONS).

Known hypersensitivity to metformin hydrochloride.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

GLUCOPHAGE and GLUCOPHAGE XR 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



Management of type 2 diabetes mellitus
: Standard release tablet or oral solution:
Dosing (Adults)
:  Start: 500 mg twice daily (give with the morning and evening meals) or 850 mg once daily; increase dosage incrementally. (A lower recommended starting dose and gradual increased dosage is recommended to minimize gastrointestinal symptoms).
Adjustment: Incremental dosing recommendations are based on dosage form:
500 mg tablet: One tablet/day at weekly intervals.
850 mg tablet: One tablet/day every other week.
Oral solution: 500 mg twice daily every other week.

Note: Doses of up to 2000 mg/day may be given in divided doses twice daily. If a dose >2000 mg/day is required, it may be better tolerated in three divided doses.

Maximum recommended dose: 2550 mg/day.

Extended release tablet:
 Initial: 500 mg once daily (with the evening meal). Dosage may be increased by 500 mg weekly. Maximum dose: 2000 mg once daily. If glycemic control is not achieved at maximum dose, may divide dose to 1000 mg twice daily. If doses >2000 mg/day are needed, switch to regular release tablets and titrate to maximum dose of 2550 mg/day.

Renal dosing:
Metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine >1.5 mg/dL in males, or >1.4 mg/dL in females and in patients with abnormal clearance.
Hepatic impairment: Avoid metformin.


Supplied:
Tablet: 500 mg, 850 mg, 1000 mg.
Extended release tablet: 500 mg, 750 mg, 1000 mg.
Oral solution - Riomet®: 100 mg/ml (118 ml, 473 ml).

Extended release brand names and strengths:
Fortamet®: 500 mg, 1000 mg
Glucophage® XR: 500 mg, 750 mg
Glumetza®: 500 mg, 1000 mg

Avandamet® (Rosiglitazone + Metformin)   top of page

These highlights do not include all the information needed to use this medication safely and effectively. See full prescribing information for ADDITONAL INFORMATION.

Management of type 2 diabetes mellitus
:
Initial (previously receiving rosiglitazone 4 mg/day): Avandamet® 2/500mg po bid. (previously receiving rosiglitazone 8 mg/day): 4/500mg po bid. (previously receiving metformin 1000 mg/day): 2/500mg po bid. (previously receiving metformin 2000 mg/day): 2/1000mg po bid.

Titrate in increments of rosiglitazone 4 mg and/or metformin 500 mg po daily.
Maximum: 8 mg/2000 mg daily.

Other:
Take with meals. When switching from metformin and rosiglitazone therapy given as separate tablets, starting dose of Avandamet is the dose of each drug previously taken. Dose titration should occur at 1 to 2 week intervals. If the dose of metformin is increased, dose titration should occur at 8 to 12 week intervals. If the dose of rosiglitazone is increased therapeutic response evaluation should be based on fasting plasma glucose values. Monitoring: renal function, baseline and at least annually.

[Supplied: 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg] .

Glucovance (Glyburide + Metformin)  top of page

These highlights do not include all the information needed to use this medication safely and effectively. See full prescribing information for ADDITONAL INFORMATION.


Management of type 2 diabetes mellitus:
Dosing
(initial):
1.25 mg/250 mg once or twice daily with meals. Dosage increases should be made in increments of 1.25 mg/250 mg per day every two weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. Glucovance 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.

Maximum recommended daily dose: 20 mg glyburide/2000 mg metformin.

Administration
: Glucovance should be given with meals and should be initiated at a low dose, with gradual dose escalation in order to avoid hypoglycemia (largely due to glyburide), to reduce GI side effects (largely due to metformin), and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.

Glucovance Use in Previously Treated Patients: Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals. In order to avoid hypoglycemia, the starting dose of Glucovance should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

Supplied:
1.25 mg/250 mg,
2.5 mg/500 mg,
5 mg/500 mg tablet

INVOKAMET ® (canagliflozin and metformin hydrochloride) tablets  top of page

Drug UPDATES:  INVOKAMET ® (canagliflozin and metformin hydrochloride) tablets, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014

Mechanism of Action:
INVOKAMET
INVOKAMET (canagliflozin and metformin hydrochloride) combines two oral antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a member of the biguanide class.

Canagliflozin
Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE).

Metformin
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, 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. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects except in special circumstances [see Warnings and Precautions (5.8)] 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.


INDICATIONS AND USAGE:  INVOKAMET is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing metformin or canagliflozin or in patients already being treated with both canagliflozin and metformin.

Limitation of use:
Not for treatment of type 1 diabetes or diabetic ketoacidosis.

HOW SUPPLIED:
Film-coated tablets:
Canagliflozin 50 mg and metformin hydrochloride 500 mg
Canagliflozin 50 mg and metformin hydrochloride 1,000 mg
Canagliflozin 150 mg and metformin hydrochloride 500 mg
Canagliflozin 150 mg and metformin hydrochloride 1,000 mg

Metaglip (Glipizide + Metformin)  top of page

These highlights do not include all the information needed to use this medication safely and effectively. See full prescribing information for ADDITONAL INFORMATION.


Management of type 2 diabetes mellitus
:
Dosing
(initial):
2.5 mg/250 mg qd with a meal. For patients whose FPG is 280 to 320 mg/dl a starting dose of Metaglip 2.5 mg/500 mg twice daily should be considered. The efficacy of Metaglip in patients whose FPG exceeds 320 mg/dl has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of one tablet per day every two weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg per day given in divided doses.

Maximum recommended daily dose: 20 mg glipizide/2000 mg metformin.


Second-Line Therapy For patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone:
2.5 mg/500 mg or 5mg/500mg bid with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of Metaglip should not exceed the daily doses of glipizide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

[Supplied: 2.5 mg/250 mg,   2.5 mg/500 mg,    5 mg/500 mg tablet ]

XIGDUO XR ® (dapagliflozin and metformin HCl extended-release) tablets  top of page

Drug UPDATES:  XIGDUO XR ® (dapagliflozin and metformin HCl extended-release) tablets, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014

Mechanism of Action:

INDICATIONS AND USAGE:   XIGDUO XR is a combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate. (1)

Limitation of use:
Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

HOW SUPPLIED:
5 mg dapagliflozin/500 mg metformin HCl extended-release
5 mg dapagliflozin/1000 mg metformin HCl extended-release
10 mg dapagliflozin/500 mg metformin HCl extended-release
10 mg dapagliflozin/1000 mg metformin HCl extended-release

Background   top of page

Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.

Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Amongst common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.

• Metformin (Glucophage) may be the best choice for patients who also have heart failure, but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients are at an increased risk of lactic acidosis.
• Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.
• Buformin also was withdrawn due to lactic acidosis risk.

Metformin is usually the first-line medication used for treatment of type 2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss as opposed to in the past, where it was prescribed after diet and exercise had failed. Initial dosing is 500 mg once daily, then if need be increased to 500 mg twice daily up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications. There is an extended release formulation available, but it is typically reserved for patients experiencing GI side effects.  [source]

References

Package insert data.

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.
David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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