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Metformin


Pronunciation

 (met FOR min)


U.S. Brand Names

 Fortamet™; Glucophage®; Glucophage® XR; Riomet™


Synonyms

 Metformin Hydrochloride


Generic Available

 Yes: Excludes solution


Canadian Brand Names

 Alti-Metformin; Apo-Metformin®; Gen-Metformin; Glucophage®; Glycon; Novo-Metformin; Nu-Metformin; PMS-Metformin; Rho®-Metformin; Rhoxal-metformin FC


Use

 Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as monotherapy when hyperglycemia cannot be managed on diet alone. May be used concomitantly with a sulfonylurea or insulin to improve glycemic control.


Use - Unlabeled/Investigational

 Treatment of HIV lipodystrophy syndrome


Pregnancy Risk Factor

 B


Pregnancy Implications

 Abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.


Lactation

 Excretion in breast milk unknown/not recommended


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); congestive heart failure requiring pharmacological management; 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 materials are utilized.


Warnings/Precautions

 Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin. Lactic acidosis should be suspected in any diabetic patient receiving metformin who has evidence of acidosis when evidence of ketoacidosis is lacking. 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.

Metformin is substantially excreted by the kidney. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function. Patients with renal function below the limit of normal for their age should not receive metformin. In elderly patients, renal function should be monitored regularly; should not be used in any patient 80 years of age unless measurement of creatinine clearance verifies normal renal function. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be suspended in patients with dehydration and/or prerenal azotemia. Therapy should be suspended for any surgical procedures (resume only after normal intake resumed and normal renal function is verified). Metformin should also be temporarily discontinued for 48 hours in patients undergoing radiologic studies involving the intravascular administration of iodinated contrast materials (potential for acute alteration in renal function).

Avoid use in patients with impaired liver function. Patient must be instructed to avoid excessive acute or chronic ethanol use. Administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality; metformin does not appear to share this risk. Safety and efficacy of metformin have been established for use in children 10 years of age; the extended release preparation is for use in patients 17 years of age.


Adverse Reactions

>10%:

Gastrointestinal: Nausea/vomiting (6% to 25%), diarrhea (10% to 53%), 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: Diaphoreses increased, vitamin B12 levels decreased (7%), flu-like syndrome, nail disorder

<1%: Megaloblastic anemia

Postmarketing and/or case reports: Lactic acidosis


Overdosage/Toxicology

 Hypoglycemia (10% of cases) or lactic acidosis (~32% of cases) may occur. Metformin is dialyzable with a clearance of up to 170 mL/minute. Hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdose is suspected. Treatment is supportive.


Drug Interactions

Drugs which tend to produce hyperglycemia (eg, diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid) may lead to a loss of glycemic control

Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) which are eliminated by renal tubular secretion could have the potential for interaction with metformin by competing for common renal tubular transport systems

Cimetidine increases (by 60%) peak metformin plasma and whole blood concentrations

Contrast agents: May increase the risk of metformin-induced lactic acidosis. Discontinue metformin prior to exposure and withhold for 48 hours.

Furosemide increased the metformin plasma and blood Cmax without altering metformin renal clearance in a single dose study


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).


Stability

 Store tablets and oral solution at 20°C to 25°C (68°F to 77°F).


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

Protein binding: Negligible

Bioavailability: Absolute: Fasting: 50% to 60%

Half-life elimination, plasma: 6.2 hours

Excretion: Urine (90% as unchanged drug)


Dosage

 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

Children 10-16 years: Management of type 2 diabetes mellitus: Oral (500 mg tablet or oral solution): Initial: 500 mg twice daily (given with the morning and evening meals); 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

Adults 17 years: Management of type 2 diabetes mellitus: Oral:

Immediate release tablet or oral solution: Initial: 500 mg twice daily (give with the morning and evening meals) 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: 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.

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.

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 of 2500 mg/day (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 dose: 2500 mg metformin; 2000 mg metformin extended release

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

 Extended release dosage form should be swallowed whole; do not crush, break, or chew. Patients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia.


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

 Target range: Adults:

Fasting blood glucose: <120 mg/dL

Glycosylated hemoglobin: <7%


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

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. 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; sudden respiratory difficulty, chest discomfort, slow or irregular heartbeat; or other adverse reactions. Breast-feeding precaution: Breast-feeding is not recommended.


Anesthesia and Critical Care Concerns/Other Considerations

 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. Metformin should be avoided in diabetic patients with heart failure.


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 diabetic patients with heart failure.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


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


Dosage Forms

Solution, oral, as hydrochloride (Riomet™): 100 mg/mL (118 mL, 473 mL) [contains saccharin; cherry flavor]

Tablet, as hydrochloride (Glucophage®): 500 mg, 850 mg, 1000 mg

Tablet, extended release, as hydrochloride: 500 mg

Fortamet™: 500 mg, 1000 mg

Glucophage® XR: 500 mg, 750 mg


References

Bailey CJ and Turner RC, "Metformin," N Engl J Med , 1996, 334(9):574-9.

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.

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.

"Standards of Medical Care for Patients With Diabetes Mellitus. American Diabetes Association," Diabetes Care , 1994, 17(6):616-23.


International Brand Names

 Adiamet® (GT); Adimet® (CZ, HU); Aglikem® (YU); Aglurab® (HR, SI, YU); Alti-Metformin (CA); Ammiformin® (TH); Apo-Metformin® (CA, NZ); Apophage® (IL); Aranka® (DE); Benofomin® (ID); Biocos® (DE); Bonformin® (DE); Cloridrato de Metformina® (BR); Clormin® (DO); Comet® (BD); Dabex® [tabs] (MX); Daomin® (BD); D.B.I.® (AR); Deson® (TH); Desugar® (AT); Diabesin® (DE); Diabetase® (DE); Diabetex® (AT); Diabetmin Retard® (SG); Diabetmin® (SG); Diabex® (AU, ID); Diaformin® (AU, BR); Diamet® (TH); Diamin® (SG); Dianben® (ES); Diaphage® (CZ, JO, RO); Diformin® (FI); Diformin Retard® (FI); Dimefor® (BR, CL, CR, DO, GT, HN, MX, PA, SV); Eraphage® (ID); espa-formin® (DE); Fintaxim® (CL); Formell® (ID); Formin® (IN, TH); Gen-Metformin (CA); Glafornil® (CL); Glifage® (BR); Gliformin® (CO); Glisulin® (CR, DO, GT, HN, PA, SV); Glucamet® (GB); Glucaminol® (AR, CO); glucobon biomo® (DE); Glucofage® (EC); Glucoformin® (BR); Glucohexal® (AU); Glucoles® (TH); Glucomet® (AU, BD, NZ, TH); Gluconormin® (CH); Glucophage® (AR, AT, AU, BE, CA, CH, CO, CZ, DE, DK, DO, FI, FR, GB, GT, HK, HR, ID, IE, IL, IT, LU, MX, NL, NO, NZ, PA, PL, RU, SE, SG, SI, SV, TH, TR, VE, YU, ZA); Glucotika® (ID); Gludepatic® (ID); Glufor® (IL); Gluformin® (CZ, HR, PL, SI, TH, YU); Glukofen® (TR); Glumin® (ID); Glustress® (TH); Gluzolyte® (TH); Glycomet® (SG); Glycon (CA); Glycoran® (JP); Glyformin® (CY); Hipoglucin® (CL); Islotin® (AR); Islotin retard® (AR); Juformin® (DE); Libraformin® (EC); Macromin® (TH); Maformin® (HU, TH); Mediabet® (DE); Meforal® (HU); Meformed® (TH); Me-F® (TH); Meglucon® (AT, DE); Meguan® (RO); Melbin® (HK, JP); Merckformin® (HU); Merck-Metformine® (BE); Mescorit® (DE); Metbay® (IT); Met® (DE); Metfen® (BD); Metfin® (CH); Metfirex® (CZ); Metfo® (BD); Metfodoc® (DE); Metfogamma® (DE, RO); Metfor-acis® (DE); Metforal® (BD, EC, IT, SG); Metforatio® (PL); Metforem® (FI); Metform AbZ® (DE); Metformax® (BE, PL); Metformin 1A Pharma® (AT, DE); Metformin AAA-Pharma® (DE); Metformina Alpharma® (PT); Metformina Anpharm® (PL); Metformina® (BR, CO); Metformina Geminis® (ES); Metformin AL® (DE, RO); Metformin Alpharma ApS® (SG); Metformin Alpharma® (DK, FI, SE); Metformin APS® (DE); Metformina Teva® (IT); Metformin-axsan® (DE); Metformin Basics® (DE); Metformin-BC® (AU); Metformin Beacons® (SG); Metformin Biochemie® (DK, FI, SE); Metformin biomo® (DE); Metformin BMS® (CZ, HR, RO); Metformin DHA® (SG); Metformin dura® (DE); Metformine Biogaran® (FR); Metformin® (GB, NO, PL); Metformin GEA® (SE); Metformin Heumann® (DE); Metformin Hexal® (DE); Metforminhydrochlorid Tyrol® (AT); Metformin Leciva® (CZ); Metformin Lich® (DE); Metformin Lindo® (DE); Metformin Meda® (SE); Metformin-Puren® (DE); Metformin RAN® (DE); Metformin-ratiopharm® (AT, DE); Metformin Sandoz® (DE); Metformin Stada® (DE); Metformin Temis® (AR); Metformin Tyrol Pharma® (AT); metformin von ct® (DE); Metfor® (TH); Metfron® (TH); Methpica® (ID); Metifor® (PL); Metiguanide® (IT); Metomin® (NZ); Metrivin® (HU); Miformin® (TH); 3M Metformin® (NZ); Neodipar® (ID); NovoMet® (AU); Novo-Metformin (CA); Nu-Metformin (CA); Orabet® (AT, DK); Oramet® (FI); PMS-Metformin (CA); Pocophage® (TH); Poli-Formin® (TH); Prophage® (TH); Rho®-Metformin (CA); Rhoxal-metformin FC (CA); Risidon® (PT); Serformin® (TH); Siamformet® (TH); Siofor® (CZ, DE, PL, RO, RU, YU); Stagid® (FR, PT); Tefor® (YU); Thiabet® (DE); Tudiab® (ID)


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