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MetFORMIN

Pronunciation

Pronunciation

(met FOR min)

Index Terms

  • Metformin HCl
  • Metformin Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral, as hydrochloride:

Riomet: 500 mg/5 mL (118 mL, 473 mL) [contains propylene glycol; strawberry flavor]

Riomet: 500 mg/5 mL (118 mL, 473 mL) [contains saccharin calcium; cherry flavor]

Tablet, Oral, as hydrochloride:

Glucophage: 500 mg, 850 mg

Glucophage: 1000 mg [scored]

Generic: 500 mg, 850 mg, 1000 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Fortamet: 500 mg, 1000 mg

Glucophage XR: 500 mg, 750 mg

Glumetza: 500 mg, 1000 mg

Generic: 500 mg, 750 mg, 1000 mg

Brand Names: U.S.

  • Fortamet
  • Glucophage
  • Glucophage XR
  • Glumetza
  • Riomet

Pharmacologic Category

  • Antidiabetic Agent, Biguanide

Pharmacology

Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)

Distribution

Vd: 654 ± 358 L; partitions into erythrocytes; concentrates in liver, kidney, and GI tract

Metabolism

Not metabolized by the liver

Excretion

Urine (90% as unchanged drug; active secretion)

Onset of Action

Within days; maximum effects up to 2 weeks

Time to Peak

Immediate release: 2 to 3 hours; Extended release: 7 hours (range: 4 to 8 hours)

Half-Life Elimination

Plasma: 4 to 9 hours; Blood ~17.6 hours

Protein Binding

Negligible

Special Populations: Renal Function Impairment

Peak and systemic exposure is increased and oral and renal Cl is decreased.

Special Populations: Elderly

Total plasma Cl is decreased, half-life is prolonged, and Cmax is increased.

Use: Labeled Indications

Diabetes mellitus, type 2: Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) when hyperglycemia cannot be managed with diet and exercise alone.

Note: If not contraindicated and if tolerated, metformin is the preferred initial pharmacologic agent for type 2 diabetes management (ADA 2016a).

Use: Unlabeled

Gestational diabetes mellitus (GDM); polycystic ovary syndrome (PCOS); prevention of type 2 diabetes mellitus

Contraindications

US labeling: 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)

Canadian labeling: Hypersensitivity to metformin or any component of the formulation; renal function unknown, renal impairment, and serum creatinine levels above the upper limit of normal range; renal disease or renal dysfunction (serum creatinine ≥136 micromol/L in males or ≥124 micromol/L in females or abnormal creatinine clearance <60 mL/minute) which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; unstable and/or insulin-dependent (type I) diabetes mellitus; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma; history of lactic acidosis (regardless of precipitating factors); excessive alcohol intake (acute or chronic); severe hepatic dysfunction or clinical or laboratory evidence of hepatic disease; cardiovascular collapse and disease states associated with hypoxemia including cardiorespiratory insufficiency, which are often associated with hyperlactacidemia; stress conditions (eg, severe infection, trauma, surgery and postoperative recovery phase); severe dehydration; pregnancy; breast-feeding

Note: The manufacturer recommends to temporarily discontinue metformin in patients undergoing radiologic studies in which intravascular iodinated contrast media are utilized.

Dosing: Adult

Diabetes mellitus, type 2: Oral: Note: Allow 1 to 2 weeks between dose titrations: Generally, clinically significant responses are not seen at doses <1,500 mg daily; however, a lower recommended starting dose and gradual increased dosage is recommended to minimize gastrointestinal symptoms.

Immediate-release tablet or solution: Adults ≥17 years: Initial: 500 mg twice daily or 850 mg once daily; titrate in increments of 500 mg weekly or 850 mg every other week; may also titrate from 500 mg twice a day to 850 mg twice a day after 2 weeks

If a dose >2,000 mg daily is required, it may be better tolerated in 3 divided doses. Maximum recommended dose: 2,550 mg daily.

Extended-release tablet: Note: If glycemic control is not achieved at maximum dose, may divide dose and administer twice daily.

Fortamet: Initial: 500 to 1,000 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2,500 mg once daily

Glucophage XR: Initial: 500 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2,000 mg once daily

Glumetza: Initial: 500 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2,000 mg once daily

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 1 to 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 daily).

Concomitant metformin and insulin therapy: Initial: Metformin 500 mg once daily; continue current insulin dose; may increase by metformin 500 mg after ~1 week and by 500 mg every week thereafter until adequate glycemic control is achieved

Maximum daily dose: Immediate release and solution: 2,550 mg metformin; Extended release: 2,000 to 2,500 mg (varies by product)

Decrease insulin dose 10% to 25% when FPG <120 mg/dL; monitor and make further adjustments as needed

Diabetes mellitus, type 2, prevention (off-label use): Immediate-release tablet or solution: Oral: Initial: 850 mg once daily; Target: 850 mg twice daily (Knowler 2002)

Polycystic ovary syndrome with anovulatory infertility (off-label use): Females: Oral:

Immediate release: 1,500 to 2,000 mg/day in 2 or 3 divided doses (Johnson 2010; Moll 2006; Morin-Papunen 2012)

Extended release: 1,000 mg twice daily (Legro 2007)

Note: Metformin should be initiated at lower doses (500 mg daily) and increased gradually over 1 to 2 weeks to the target dose to minimize adverse effects (eg, GI intolerance) (Johnson 2010; Legro 2007; Moll 2006; Morin-Papunen 2012)

Polycystic ovary syndrome with menstrual irregularities (off-label use): Females: Oral: Immediate release: 500 mg 2 or 3 times daily, up to 1,000 mg twice daily (Costello 2007; Morin-Papunen 2003; Meyer 2007; Moghetti 2000). The dose of metformin should be increased gradually to minimize GI adverse effects (Meyer 2007)

Note: When metformin is used, cyclic progestin therapy may be added for the first 6 months of metformin treatment, until regular cycles are established.

Prevention of ovarian hyperstimulation syndrome with polycystic ovary syndrome (off-label use): Females: Oral: Immediate release: 1,000 mg to 2,550 mg per day as 500 mg 2 or 3 times per day or 850 mg 2 or 3 times per day (Palomba 2013; Palomba 2011; Tang 2006; Tso 2014). The dose of metformin should be increased gradually to minimize GI adverse effects.

Note: Pretreatment with metformin may be started as early as 16 weeks prior (but typically 4 to 5 weeks prior) to as late as the first day of gonadotropin-releasing hormone (GnRH) agonist administration; some studies continued metformin therapy during gonadotropin ovarian stimulation (Tso 2014).

Dosing: Geriatric

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.

Dosing: Pediatric

Diabetes mellitus, type 2: Oral: Note: Allow 1 to 2 weeks between dose titrations: Generally, clinically significant responses are not seen at doses <1,500 mg daily; however, a lower recommended starting dose and gradual increased dosage is recommended to minimize gastrointestinal symptoms.

Immediate-release tablet or solution:

Children ≥10 years and Adolescents ≤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 2,000 mg daily

Adolescents ≥17 years: Refer to adult dosing.

Extended-release tablet: Adolescents ≥17 years: Note: If glycemic control is not achieved at maximum dose, may divide dose and administer twice daily.

Fortamet: Initial: 500 to 1,000 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2,500 mg once daily

Glucophage XR: Initial: 500 mg once daily; dosage may be increased by 500 mg weekly; maximum dose: 2,000 mg once daily

Dosing: Renal Impairment

Manufacturer's labeling:

Serum creatinine (SCr) ≥1.5 mg/dL (males) or ≥1.4 mg/dL (females): Use is contraindicated.

Abnormal CrCl (U.S. labeling: Not defined; Canadian labeling: <60 mL/minute): Use is contraindicated.

Alternate recommendations: Note: The United Kingdom National Institute for Health and Clinical Excellence (NICE) Guidelines recommends prescribing metformin with caution in those patients who are at risk of sudden deterioration in renal function and at risk of an estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2 (NICE 2008). Some evidence suggests that use of metformin is unsafe when eGFR <30 mL/minute/1.73 m2 (calculated using MDRD) (Shaw 2007). A review of the available data by members of the American Diabetes Association proposed the following recommendations based on eGFR (Lipska 2011):

eGFR ≥60 mL/minute/1.73 m2: No contraindications, monitor renal function annually

eGFR ≥45 to <60 mL/minute/1.73 m2: Continue use; monitor renal function every 3 to 6 months

eGFR ≥30 to <45 mL/minute/1.73 m2: In patients currently receiving metformin, use with caution, consider dosage reduction (eg, 50% reduction or 50% of maximal dose), monitor renal function every 3 months. Do not initiate therapy in patients with eGFR <45 mL/minute/1.73 m2

eGFR <30 mL/minute/1.73 m2: Discontinue use.

Dosing: Hepatic Impairment

The manufacturer recommends avoiding metformin since liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett 2010; Zhang 2014).

Administration

Administer with a meal (to decrease GI upset).

Extended release: Swallow whole; do not crush, break, or chew. Administer once daily doses with the evening meal. Fortamet should also be administered with a full glass of water.

Dietary Considerations

Drug may cause GI upset; take with food (to decrease GI upset). Take at the same time(s) 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.

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.

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. 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. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Adverse Reactions

>10%: Gastrointestinal: Diarrhea (IR tablet: 53%; ER tablet: 10%), nausea and vomiting (IR tablet: 26%; ER tablet: 7%), flatulence (12%)

1% to 10%:

Cardiovascular: Chest discomfort (1% to 5%), flushing (1% to 5%), palpitations (1% to 5%)

Central nervous system: Headache (6%), chills (1% to 5%), dizziness (1% to 5%), taste disorder (1% to 5%)

Dermatologic: Diaphoresis (1% to 5%), nail disease (1% to 5%), skin rash (1% to 5%)

Endocrine & metabolic: Decreased vitamin B12 serum concentrate (7%), hypoglycemia (1% to 5%)

Gastrointestinal: Dyspepsia (≤1% to 7%), abdominal distress (6%), abdominal distention (1% to 5%), abdominal pain (1% to 5%), abnormal stools (1% to 5%), constipation (1% to 5%), heartburn (≤1% to 5%)

Neuromuscular & skeletal: Weakness (9%), myalgia (1% to 5%)

Respiratory: Dyspnea (1% to 5%), flu-like symptoms (1% to 5%), upper respiratory tract infection (1% to 5%)

<1% (Limited to important or life-threatening): Lactic acidosis, megaloblastic anemia

ALERT: U.S. Boxed Warning

Lactic acidosis

Lactic acidosis is a rare but serious metabolic complication that can occur because of metformin accumulation during treatment with metformin; 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 or more), 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 of 5 mcg/mL or more are generally found.

The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases per 1,000 patient-years, with approximately 0.015 fatal cases per 1,000 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 function impairment, including 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 (CHF) requiring pharmacologic management, in particular those with unstable or acute CHF 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. Therefore, the risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, accompany treatment of elderly patients with careful monitoring of renal function. Do not initiate metformin treatment in patients 80 years of age and older unless measurement of creatinine clearance (CrCl) demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis. In addition, promptly withhold metformin in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because hepatic function impairment may significantly limit the ability to clear lactate, generally avoid using metformin in patients with clinical or laboratory evidence of hepatic disease. Caution patients against excessive alcohol intake, either acute or chronic, when taking metformin because alcohol potentiates the effects of metformin on lactate metabolism. In addition, temporarily discontinue metformin prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis is often 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 health care provider must be aware of the possible importance of such symptoms. Instruct patients to notify their health care provider immediately if these symptoms occur. Withdraw metformin 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, GI symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of GI symptoms could be caused by lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal (ULN) but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explained by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

Suspect lactic acidosis 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, immediately discontinue the drug and promptly institute general supportive measures. Because metformin 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.

Warnings/Precautions

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: [US Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin that requires urgent care and hospitalization. The risk is increased in patients with acute congestive heart failure, dehydration, excessive alcohol intake, hepatic or renal impairment, or sepsis. Symptoms may be nonspecific (eg, abdominal distress, malaise, myalgia, respiratory distress, somnolence); low pH, increased anion gap and elevated blood lactate may be observed. Discontinue immediately if acidosis is suspected. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Vitamin B12 concentrations: May impair vitamin B12 absorption, particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with discontinuation of therapy or supplementation. Monitor vitamin B12 serum concentrations periodically with long-term therapy.

Disease-related concerns:

• Diabetes mellitus, type 1: Not indicated for use in patients with type 1 diabetes mellitus (insulin dependent, IDDM) due to lack of efficacy in this population.

• Diabetic ketoacidosis: Not indicated for use in patients with diabetic ketoacidosis (DKA) due to lack of efficacy in this patient population.

• 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: Use with caution 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).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Do not initiate in patients ≥80 years of age unless normal renal function is confirmed; risk of lactic acidosis may be increased.

Dosage form specific issues:

• Extended release tablet: Insoluble tablet shell (Glumetza 1,000 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: The FDA recommends temporary discontinuation of metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015). Temporary discontinuation of metformin should occur at the time of or prior to the procedure, withheld for 48 hours following the procedure, and then resumed only when normal renal function is confirmed.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Surgical procedures: Therapy should be suspended for any surgical procedures (Canadian labeling recommends discontinuing use 48 hours prior to surgical procedures), excluding minor procedures not associated with restricted food and fluid intake. Restart only after normal oral intake resumed and normal renal function is verified.

Monitoring Parameters

Urine for glucose and ketones, fasting blood glucose, hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016c]), and fructosamine. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function should be performed, at least annually (Canadian labeling recommends monitoring renal function every 6 months or more frequently if necessary). Monitor vitamin B12 serum concentrations periodically with long-term therapy.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Metformin has been found to cross the placenta in concentrations which may be comparable to those found in the maternal plasma. Pharmacokinetic studies suggest that clearance of metformin may increase during pregnancy and dosing may need adjusted in some women when used during the third trimester (Charles 2006; de Oliveira Baraldi 2011; Eyal 2010; Gardiner 2003; Hughes 2006; Vanky 2005).

An increased risk of birth defects or adverse fetal/neonatal outcomes has not been observed following maternal use of metformin for GDM or type 2 diabetes when glycemic control is maintained (Balani 2009; Coetzee 1979; Coetzee 1984; Ekpebegh 2007; Niromanesh 2012; Rowan 2008; Rowan 2010; Tertti 2008). In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008).

Metformin may be used to treat GDM when nonpharmacologic therapy is not effective in maintaining glucose control (ACOG 2013). Metformin or lifestyle intervention may also be used in women with a history of GDM who later develop prediabetes in order to prevent or delay type 2 diabetes (ADA 2015).

Metformin is recommended to treat insulin resistance associated with PCOS; however, its use may also restore spontaneous ovulation. Women with PCOS who do not desire to become pregnant should use effective contraception. Although studied for use in women with anovulatory PCOS, there is no evidence that it improves live birth rates or decreases pregnancy complications. Routine use to treat infertility related to PCOS is not currently recommended (ACOG 2009; Fauser 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, flatulence, nausea, vomiting, or loss of strength and energy. Have patient report immediately to prescriber signs of too much lactic acid in the blood (lactic acidosis; fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), or severe abdominal pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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