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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
MetFORMIN may be confused with metroNIDAZOLE
Glucophage® may be confused with Glucotrol®, Glutofac®
Pronunciation
(met FOR min)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes solution
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as monotherapy when hyperglycemia cannot be managed with diet and exercise alone. In adults, may be used concomitantly with a sulfonylurea or insulin to improve glycemic control.
Use: Unlabeled/Investigational
Gestational diabetes mellitus (GDM); polycystic ovary syndrome (PCOS)
Pregnancy Risk Factor
B
Pregnancy Considerations
Adverse events have not been observed in animal studies; therefore, metformin is classified as pregnancy category B. Metformin has been found to cross the placenta in levels which may be comparable to those found in the maternal plasma. Pharmacokinetic studies suggest that clearance of metformin may be increased during pregnancy and dosing may need adjusted in some women when used during the third trimester.Fetal, neonatal, and maternal outcomes have been evaluated following maternal use of metformin for the treatment of GDM and type 2 diabetes. Available information suggests that metformin use during pregnancy may be safe as long as good glycemic control is maintained; however, many studies used metformin during the second or third trimester only. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Until additional safety and efficacy data are obtained, the use of oral agents is generally not recommended as routine management of GDM or type 2 diabetes mellitus during pregnancy. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.Metformin has also been evaluated for the treatment of PCOS, a syndrome which may exhibit oligomenorrhea and in some women, hyperinsulinemia. When used to treat infertility related to PCOS, current guidelines restrict the use of metformin to women with glucose intolerance.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Low amounts of metformin (generally ?1% of the weight-adjusted maternal dose) are excreted into breast milk. Breast-feeding is not recommended by the manufacturer. Because breast milk levels of metformin stay relatively constant, avoiding nursing around peak plasma concentrations in the mother would not be helpful in reducing metformin exposure to the infant. Growth and development were not found to be affected in infants born to mothers with PCOS and who took metformin while breast-feeding.
Contraindications
Hypersensitivity to metformin or any component of the formulation; renal disease or renal dysfunction (serum creatinine ?1.5 mg/dL in males or ?1.4 mg/dL in females) or abnormal creatinine clearance from any cause, including shock, acute myocardial infarction, or septicemia; acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis)
Note: Temporarily discontinue in patients undergoing radiologic studies in which intravascular iodinated contrast media are utilized.
Warnings/Precautions
Boxed warnings:
• Lactic acidosis: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Cardiovascular mortality: Administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality; metformin does not appear to share this risk.
• Lactic acidosis: [U.S. Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in clinical situations predisposing to hypoxemia, including conditions such as cardiovascular collapse, respiratory failure, acute myocardial infarction, acute congestive heart failure, and septicemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.
Disease-related concerns:
• Heart failure: Use caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable or acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.
• Hepatic impairment: Avoid use in patients with impaired liver function due to potential for lactic acidosis.
• Renal impairment: Metformin is substantially excreted by the kidney; patients with renal function below the limit of normal for their age should not receive therapy. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Special populations:
• Elderly: Metformin should not be initiated in patients ?80 years of age unless normal renal function is confirmed.
• Pediatrics: Safety and efficacy have not been established in children <10 years of age. In addition, safety and efficacy for the extended release preparation have not been established in children <17 years of age.
Dosage form specific issues:
• Extended release tablet: Insoluble tablet shell (Glumetza™ 1000 mg tablet) may remain intact and be visible in the stool. Other extended released tablets (Fortamet®, Glucophage® XR, Glumetza™ 500 mg) may appear in the stool as a soft mass resembling the tablet.
Other warnings/precautions:
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.
• Iodinated contrast: Therapy should be temporarily discontinued prior to or at the time of intravascular administration of iodinated contrast media (potential for acute alteration in renal function). Metformin should be withheld for 48 hours after the radiologic study and restarted only after renal function has been confirmed as normal.
• Surgical procedures: Therapy should be suspended for any surgical procedures (resume only after normal intake resumed and normal renal function is verified).
Adverse Reactions
>10%:
Gastrointestinal: Diarrhea (10% to 53%), nausea/vomiting (7% to 26%), flatulence (12%)
Neuromuscular & skeletal: Weakness (9%)
1% to 10%:
Cardiovascular: Chest discomfort, flushing, palpitation
Central nervous system: Headache (6%), chills, dizziness, lightheadedness
Dermatologic: Rash
Endocrine & metabolic: Hypoglycemia
Gastrointestinal: Indigestion (7%), abdominal discomfort (6%), abdominal distention, abnormal stools, constipation, dyspepsia/ heartburn, taste disorder
Neuromuscular & skeletal: Myalgia
Respiratory: Dyspnea, upper respiratory tract infection
Miscellaneous: Diaphoresis increased, vitamin B12 levels decreased (7%), flu-like syndrome, nail disorder
<1%: Megaloblastic anemia
Postmarketing and/or case reports: Lactic acidosis, leukocytoclastic vasculitis, pneumonitis
Drug Interactions
Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Cimetidine: May decrease the excretion of MetFORMIN. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Risk D: Consider therapy modification
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol (incidence of lactic acidosis may be increased; may cause hypoglycemia).
Food: Food decreases the extent and slightly delays the absorption. May decrease absorption of vitamin B12 and/or folic acid.
Herb/Nutraceutical: Caution with chromium, garlic, gymnema (may cause hypoglycemia).
Storage
Oral solution: Store at 15°C to 30°C (59°F to 86°F).
Tablets: Store at 20°C to 25°C (68°F to 77°F); excursion permitted to 15°C to 30°C (59°F to 86°F). Protect from light and moisture.
Mechanism of Action
Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)
Pharmacodynamics/Kinetics
Onset of action: Within days; maximum effects up to 2 weeks
Distribution: Vd: 654 ± 358 L; partitions into erythrocytes
Protein binding: Negligible
Metabolism: Not metabolized by the liver
Bioavailability: Absolute: Fasting: 50% to 60%
Half-life elimination: Plasma: 4-9 hours
Time to peak, serum: Immediate release: 2-3 hours; Extended release: 7 hours (range: 4-8 hours)
Excretion: Urine (90% as unchanged drug; active secretion)
Dosage
Type 2 diabetes management: Note: Allow 1-2 weeks between dose titrations: Generally, clinically significant responses are not seen at doses <1500 mg daily; however, a lower recommended starting dose and gradual increased dosage is recommended to minimize gastrointestinal symptoms.
Immediate release tablet or solution: Oral:
Children 10-16 years: Initial: 500 mg twice daily; increases in daily dosage should be made in increments of 500 mg at weekly intervals, given in divided doses, up to a maximum of 2000 mg/day
Chidlren ?17 years and Adults: Initial: 500 mg twice daily or 850 mg once daily; increase dosage incrementally.
Incremental dosing recommendations 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
Doses of up to 2000 mg/day may be given 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: Oral: Note: If glycemic control is not achieved at maximum dose, may divide dose and administer twice daily.
Children ?17 years and Adults:
Fortamet®: Initial: 1000 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2500 mg once daily
Glucophage® XR: Initial: 500 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2000 mg once daily
Adults: Glumetza™: Initial: 1000 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2000 mg once daily
Elderly: The initial and maintenance dosing should be conservative, due to the potential for decreased renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin. Do not use in patients ?80 years of age unless normal renal function has been established.
Transfer from other antidiabetic agents: No transition period is generally necessary except when transferring from chlorpropamide. When transferring from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant metformin and oral sulfonylurea therapy: If patients have not responded to 4 weeks of the maximum dose of metformin monotherapy, consider a gradual addition of an oral sulfonylurea, even if prior primary or secondary failure to a sulfonylurea has occurred. Continue metformin at the maximum dose. If adequate response has not occurred following 3 months of metformin and sulfonylurea combination therapy, consider switching to insulin with or without metformin.
Failed sulfonylurea therapy: Patients with prior failure on glyburide may be treated by gradual addition of metformin. Initiate with glyburide 20 mg and metformin 500 mg daily. Metformin dosage may be increased by 500 mg/day at weekly intervals, up to a maximum metformin dose (dosage of glyburide maintained at 20 mg/day).
Concomitant metformin and insulin therapy: Initial: 500 mg metformin once daily, continue current insulin dose; increase by 500 mg metformin weekly until adequate glycemic control is achieved
Maximum daily dose: Immediate release and solution: 2550 mg metformin; Extended release: 2000-2500 mg (varies by product)
Decrease insulin dose 10% to 25% when FPG <120 mg/dL; monitor and make further adjustments as needed
Dosing adjustment/comments in renal impairment: The plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. Per the manufacturer, 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. Clinically, it has been recommended that metformin be avoided in patients with Clcr <60-70 mL/minute (DeFronzo, 1999).
Dosing adjustment in hepatic impairment: Avoid metformin; liver disease is a risk factor for the development of lactic acidosis during metformin therapy.
Administration: Oral
Extended release dosage form should be swallowed whole; do not crush, break, or chew; administer with food (to decrease GI upset). Administer Fortamet® with a glass of water.
Monitoring Parameters
Urine for glucose and ketones, fasting blood glucose, and hemoglobin A1c. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function should be performed, at least annually. Check vitamin B12 and folate if anemia is present.
Reference Range
Recommendations for glycemic control in adults with diabetes:
Hb A1c: <7%
Preprandial capillary plasma glucose: 70-130 mg/dL
Peak postprandial capillary blood glucose: <180 mg/dL
Blood pressure: <130/80 mm Hg
Dietary Considerations
Drug may cause GI upset; take with food (to decrease GI upset). Take at the same time each day. Dietary modification based on ADA recommendations is a part of therapy. Monitor for signs and symptoms of vitamin B12 and/or folic acid deficiency; supplementation may be required.
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Take as directed (may take with food to decrease GI upset). Do not chew or crush tablets. Parts of extended-release tablets may be excreted in the stool (normal). Do not change dosage or discontinue without consulting prescriber. Avoid overuse of alcohol (could cause severe reaction). It is important to follow dietary and lifestyle recommendations of prescriber. You will be instructed in signs of hypo- or hyperglycemia by prescriber or diabetic educator. May cause drowsiness or dizziness (use caution driving or engaging in potentially hazardous tasks until response to drug is known); nausea or vomiting (taking with meals, eating small frequent meals, frequent mouth care, or sucking lozenges may help); or abdominal distention, flatulence, diarrhea, constipation, or heartburn (if these persist consult prescriber for approved medication). Report immediately unusual weakness or fatigue; unusual muscle pain; persistent GI discomfort; dizziness or lightheadedness; unusual somnolence; sudden respiratory difficulty, chest discomfort, slow or irregular heartbeat; or other adverse reactions. Breast-feeding precaution: Breast-feeding is not recommended.
Geriatric Considerations
Limited data suggest that metformin's total body clearance may be decreased and AUC and half-life increased in elderly patients; presumably due to decreased renal clearance. Metformin has been well tolerated by the elderly but lower doses and frequent monitoring are recommended. In one study of elderly subjects, its effects could not be distinguished from tolbutamide, except for weight loss. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin. Do not use in patients ?80 years of age unless normal renal function has been established. Intensive glucose control (Hb A1c <6.5) has been linked to increased all cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: While megaloblastic anemia has been rarely seen with metformin, if suspected, vitamin B12 deficiency should be excluded. Metformin has a large volume of distribution in liver, kidney, and GI tract where concentration is much larger than in the plasma.
Lactic acidosis is an uncommon side effect in patients without renal or respiratory insufficiency, hepatic failure, or conditions that predispose to hypoxemia.
Cardiovascular Considerations
Metformin, alone or in combination with other agents (sulfonylurea), is effective in the management of diabetes. Lactic acidosis is an uncommon side effect in patients without renal or respiratory insufficiency, hepatic failure, or conditions that predispose to hypoxemia. As heart failure may affect renal and pulmonary function, metformin should be avoided or used with caution in patients with diabetes and heart failure.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Taste disorder.
Metformin-dependent patients with diabetes (noninsulin dependent, Type 2) should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia; use caution with clozapine and carbamazepine; concurrent use with psychotropics may produce additive sedation
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other prescriptions, OTC medications, or herbal products patient may be taking (eg, anything that may effect glucose levels). Assess results of laboratory tests, therapeutic effectiveness, and adverse response (eg, assess for signs and symptoms of vitamin B12 and/or folic acid deficiency; supplementation may be required) during therapy. Teach patient (or refer patient to diabetic educator for instruction) in appropriate use, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, oral, as hydrochloride:
Riomet®: 100 mg/mL (118 mL, 473 mL) [contains saccharin; cherry flavor]
Tablet, as hydrochloride: 500 mg, 850 mg, 1000 mg
Glucophage®: 500 mg, 850 mg, 1000 mg
Tablet, extended release, as hydrochloride: 500 mg, 750 mg
Fortamet®: 500 mg, 1000 mg
Glucophage® XR: 500 mg
Glumetza™: 500 mg, 1000 mg
Pricing: U.S. (www.drugstore.com)
Solution (Riomet)
500 mg/5 mL (473): $99.90
Tablet, 24-hour (Fortamet)
500 mg (60): $134.39
1000 mg (60): $302.39
Tablet, 24-hour (Glucophage XR)
500 mg (60): $69.99
750 mg (30): $53.99
Tablet, 24-hour (Glumetza)
500 mg (100): $166.01
Tablet, 24-hour (MetFORMIN HCl)
500 mg (90): $18.99
750 mg (30): $32.99
Tablets (Glucophage)
500 mg (60): $69.99
850 mg (60): $113.29
1000 mg (60): $141.08
References
American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Writing Committee, “American Association of Clinical Endocrinologists Position Statement on Metabolic and Cardiovascular Consequences of Polycystic Ovary Syndrome,” Endocr Pract , 2005, 11(2):126-34.
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2009,” Diabetes Care, 2009, 32(Suppl 1):13-61.
Bailey CJ and Turner RC, “Metformin,” N Engl J Med, 1996, 334(9):574-9.
Coetzee EJ and Jackson WP, "Metformin in Management of Pregnant Insulin-Independent Diabetics," Diabetologia, 1979, 16(4):241-5.
DeFronzo RA, “Pharmacologic Therapy for Type 2 Diabetes Mellitus,” Ann Intern Med, 1999, 131(4):281-303.
Dunn CJ and Peters DH, “Metformin: A Review of Its Pharmacologic Properties and Therapeutic Use in Diabetes Mellitus,” Drugs, 1995, 49(5):721-49.
Hughes RC and Rowan JA, "Pregnancy in Women With Type 2 Diabetes: Who Takes Metformin and What Is the Outcome?" Diabet Med, 2006, 23(3):318-22.
Josephkutty S and Potter JM, “Comparison of Tolbutamide and Metformin in Elderly Diabetic Patients,” Diabet Med, 1990, 7(16):510-4.
Lalau JD, Vermersch A, Hary L, et al, “Type 2 Diabetes in the Elderly: An Assessment of Metformin,” Int J Clin Pharmacol Ther Toxicol, 1990, 28(8):329-32.
Nestler JE, “Metformin for the Treatment of the Polycystic Ovary Syndrome,” N Engl J Med, 2008, 358(1):47-54.
Rowan JA, Hague WM, Gao W, et al, “Metformin Versus Insulin for the Treatment of Gestational Diabetes,” N Engl J Med, 2008, 358(19):2003-15.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
Content last modified September 2009
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