Certain manufacturers' metformin extended-release products are being recalled because they contain a trace amount of the impurity N-Nitrosodimethylamine (NDMA), a known animal and suspected human carcinogen.
More information may be found at https://www.fda.gov/news-events/press-announcements/fda-alerts-patients-and-health-care-professionals-nitrosamine-impurity-findings-certain-metformin and https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
If metformin-associated lactic acidosis is suspected, immediately discontinue metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Antipsychotic-induced weight gain, treatment (off-label use):
Immediate release: Oral: Dosage range studied in trials: 750 mg to 2 g daily in 2 to 3 divided doses. Doses up to 2.55 g/day have also been used. To minimize GI adverse effects, most trials initiated therapy with 250 mg or 500 mg twice daily or 850 mg once daily, and increased the dose gradually based on tolerability (Baptista 2007; Chen 2013; Das 2012; de Silva 2016; Jarskog 2013; Wang 2012; Zheng 2015).
Extended release: Oral: Maintenance dosage range in trials: 1 to 2 g once daily. To minimize GI adverse effects, trials initiated therapy with 500 mg once daily and titrated dosage upwards in 500 mg increments every 2 to 6 weeks based on tolerability (Carrizo 2009; Rado 2016).
Diabetes mellitus, type 2, prevention (off-label use):
Note: For select patients with prediabetes, particularly for those with BMI ≥35 kg/m2, age <60 years, and patients with prior gestational diabetes mellitus, in whom lifestyle interventions fail to improve glycemic indices (ADA 2020; Robertson 2021).
Immediate release: Oral: Initial: 850 mg once daily for 1 month, then increase to 850 mg twice daily; unless GI adverse effects warrant a longer titration period (Knowler 2002)
Diabetes mellitus, type 2, treatment:
Note: In patients in whom glycemic targets are not met despite diet, exercise, and metformin, combination therapy is necessary to achieve optimal results (Wexler 2021a).
Immediate release: Oral:
Initial: 500 mg once or twice daily or 850 mg once daily (Nathan 2009)
Dosage adjustments: The dose should be increased gradually to minimize GI adverse effects. Titration strategies vary widely, but usually done in 500 mg or 850 mg increments every 7 days (range: 5 days to 1 month).
Usual maintenance dosage: 1 g twice daily or 850 mg twice daily (Nathan 2009)
Maximum: 2.55 g/day. Modest additional benefit has been observed with doses up to ~2.5 g/day; however, GI adverse effects may limit use (Nathan 2009). If doses >2 g/day are needed, consider administering in 3 divided doses to minimize GI adverse effects.
Extended release: Oral:
Initial: 500 mg to 1 g once daily
Dosage adjustments: The dose should be increased gradually to minimize GI adverse effects. Titration strategies vary widely, but usually done in 500 mg increments every 7 days (range: 7 days to 6 weeks).
Maximum: 2 g/day. If glycemic control is not achieved at maximum dose given once daily, may divide maximum dose and administer twice daily.
Gestational diabetes mellitus, treatment (alternative agent) (off-label use): Immediate release: Oral: Initial: 500 mg once or twice daily; increase dosage to meet glycemic targets, typically over 1 to 2 weeks, up to a maximum of 2 to 2.5 g daily in 2 to 3 divided doses. If targets not achieved with metformin alone, insulin may be added (Nachum 2017; Niromanesh 2012; Rowan 2008; Tertti 2013). Note: Insulin is the preferred medication for gestational diabetes as it does not cross the placenta to a measurable extent; all oral agents lack long-term safety data (ADA 2020).
Polycystic ovary syndrome (PCOS): Note: Metformin is no longer recommended for anovulatory infertility in patients with PCOS (ASRM 2017).
Oligomenorrhea due to PCOS, treatment (alternative agent) (off-label use): Immediate release: Oral: Dosage range studied in trials: 1.5 to 2 g daily in 2 to 3 divided doses; to minimize GI adverse effects, most trials initiated therapy with 500 mg once or twice daily and gradually increased the dose in 500 mg increments every 7 days (Costello 2007; Moghetti 2000; Morin-Papunen 2003; Nestler 2002). Note: Cyclic progestin therapy may be added for the first 6 months of metformin treatment, until regular cycles are established (Barbieri 2018).
Ovarian hyperstimulation syndrome (OHSS) in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), prevention (alternative agent) (off-label use): Immediate release: Oral: Dosage range studied in trials: 1 to 2.55 g daily in 2 to 3 divided doses (Doldi 2006; Palomba 2011; Palomba 2013; Tang 2006; Tso 2014). Note: In most trials, metformin was used as a pretreatment and coadministered with gonadotropins; one trial coadministered metformin with gonadotropins only. Metformin was given until oocyte retrieval, hCG administration, or embryo transfer in most trials; in some trials, it was given until pregnancy test or 12 weeks' gestation (Palomba 2013).
Metformin conversion recommendations:
Conversion from IR to ER dosage forms: Patients receiving metformin immediate-release may be switched to metformin extended-release once daily at the same total daily dose, up to 2 g once daily. However, in patients who are doing well with immediate-release metformin, some experts recommend they continue using it, as there is little additional benefit documented with ER tablets (Wexler 2021b).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS
Altered kidney function:
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary. Monitor renal function at least annually.
eGFR >45 to <60 mL/minute/1.73 m2: No dosage adjustment necessary. Metformin plasma concentrations may be higher compared to patients with an eGFR ≥60 mL/minute/1.73 m2; increase monitoring of renal function (eg, every 3 to 6 months) (ADA [Lipska 2011]; KDIGO 2020; Lalau 2018).
eGFR 30 to 45 mL/minute/1.73 m2:
Initiation of therapy: Use generally not recommended (AACE [Garber 2020]; ADA 2020; manufacturer's labeling); however, initial therapy with 500 mg once daily with the evening meal titrated to 500 mg twice daily, if tolerated, with close monitoring of kidney function has been recommended by some experts (Lalau 2018; Wexler 2021b).
Continuation of existing therapy: May continue at a reduced dose up to a maximum of 500 mg twice daily with close monitoring of kidney function (ADA [Lipska 2011]; Inzucchi 2014).
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
Acute kidney injury during therapy: If acute kidney injury occurs or if risk factors are present (eg, severe vomiting or diarrhea), instruct patient to temporarily hold metformin (Diabetes Canada 2018; Wexler 2021b).
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 patients with diabetes and 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; Crowley 2017; Zhang 2014).
(For additional information see "Metformin: Pediatric drug information")
Diabetes mellitus, type 2; treatment: Note: Allow 1 to 2 weeks between dose titrations. Generally, clinically significant responses are not seen at doses less than 1,500 to 2,000 mg/day (AAP [Copeland 2013]); however, a lower recommended starting dose with a gradual increase in dosage is recommended to minimize gastrointestinal symptoms.
Immediate-release tablet or solution: Children ≥10 years and Adolescents: Oral: Initial: 500 to 1,000 mg once daily or 500 mg twice daily; increase dose every 1 to 2 weeks as tolerated in 500 to 1,000 mg increments; maximum dose: 1,000 mg twice daily or 850 mg 3 times daily (AAP [Copeland 2013]; ADA [Arslanian 2018]; ISPAD [Zeitler 2018]; manufacturer labeling).
Extended-release: Note: Fewer gastrointestinal effects may be seen with extended-release products; however, no pediatric studies have compared extended-release products to standard metformin (ADA [Arslanian 2018]).
Children ≥10 years and Adolescents:
Oral suspension: Oral: 500 mg once daily in the evening; titrate dose in 500 mg increments at weekly intervals as tolerated; maximum daily dose: 2,000 mg/day once daily with evening meal.
Tablets: Limited data available: Oral: Initial: 500 to 1,000 mg once daily for 7 to 14 days; may increase dose in 500 to 1,000 mg increments every 1 to 2 weeks as tolerated; maximum daily dose: 2,000 mg/day (AAP [Copeland 2013]; ADA [Arslanian 2018]; ISPAD [Zeitler 2018]). Note: If glycemic control is not achieved at maximum dose, may divide dose and administer twice daily.
Surgical patients (ISPAD [Jefferies 2018]):
Minor surgeries: Discontinue metformin the day of surgery; monitor glucose closely; rapid-acting SUBQ insulin may be required. Continue to withhold metformin for 48 hours following surgery and until normal renal function has been confirmed.
Major surgeries (eg, lasting >2 hours): Discontinue metformin 24 hours prior to surgery; monitor glucose closely; IV insulin infusion may be needed for hyperglycemia during surgery. Continue to withhold metformin for 48 hours following surgery and until normal renal function has been confirmed.
Obesity; severe, adjunct therapy with lifestyle interventions: Limited data available; data has shown modest efficacy; reported mean BMI reduction −0.86 to −1.16 kg/m2, although reported efficacy endpoints/outcomes in trials are variable (Endocrine Society [Styne 2017]; McDonagh 2014; USPSTF 2017). Overall, due to limited efficacy, some experts do not consider metformin a weight loss treatment option for pediatric obesity (Endocrine Society [Styne 2017]). Optimal treatment duration not established; duration in trials varied from 3 to 12 months. Daily multivitamin supplement may be considered with therapy (Matson 2012).
Immediate release: Dosing regimens variable: Children ≥6 years and Adolescents: Oral: Initial: 500 mg once or twice daily, may titrate upward at weekly intervals by 500 mg/day increments; reported final doses: 1,000 to 2,000 mg/day in 2 divided doses; a meta-analysis showed that metformin 2,000 mg/day intervention was most identified as most effective relative to lower doses or lifestyle modifications in adolescents without diabetes (Hui 2019; Kendall 2013; USPSTF 2017; Yanovski 2011). Age-dependent efficacy findings are conflicting; some data suggests that metformin may have greater efficacy in prepubertal children and others have shown a greater effect in pubertal subjects (11 to 17 years) (Pastor-Villaescusa 2017; Warnakulasuriya 2018). A low dose (850 mg/day) over a prolonged period (24 months) showed positive effects on body composition (weight and BMI standard deviation scores) and other metabolic and inflammatory markers (eg, fat mass, liver fat, leptin, highly sensitive C-reactive protein) in a small, placebo-controlled trial of 22 subjects (metformin=13; age range: 6 to 13 years) (Bassols 2019).
Extended release: Metformin XR: Adolescents: Oral: Initial: 500 mg once daily with dinner for 2 weeks; increase to 1,000 mg once daily for 2 weeks, and then 2,000 mg once daily; may slow titration if adverse gastrointestinal effects (Glaser Pediatric Research Network [Wilson 2010]).
Weight gain, atypical antipsychotic-induced; treatment: Limited data available:
Immediate release: Note: In trials, all patients were diagnosed with autism spectrum disorder; trials used metformin oral solution (Riomet) and slowly titrated the dose to minimize GI effects and maximize tolerability. After 16 weeks of therapy, patients receiving metformin had a statistically significant decrease in BMI z-scores (primary efficacy outcome) as well as other secondary outcomes (eg, raw weight, BMI) compared to placebo. A 16-week, open-label extension study showed results achieved in the treatment group were maintained without further decreases (Anagnostou 2016; Handen 2017).
6 to 9 years: Oral: Initial: 250 mg with evening meal for 1 week, then 250 mg twice daily for 1 week, then 500 mg twice daily.
10 to 17 years: Oral: Initial: 250 mg with evening meal for 1 week, then 250 mg twice daily for 1 week, then 500 mg twice daily for 1 week, then 850 mg twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥10 years and Adolescents: Oral: Immediate release, extended release:
eGFR >45 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to 45 mL/minute/1.73 m2:
Preexisting impairment: Initiation of therapy is not recommended.
During therapy:
If eGFR falls between 30 and <45 mL/minute/1.73 m2: Consider risk/benefit ratio for continuing therapy.
If eGFR falls to <30 mL/minute/1.73 m2:Discontinue therapy.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
Children ≥10 years and Adolescents: Avoid metformin; liver disease is a risk factor for the development of lactic acidosis during metformin therapy.
Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Kit, Combination:
D-Care DM2: Extended release tablet, as hydrochloride: 500 mg [DSC]
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]
Generic: 500 mg/5 mL (118 mL, 473 mL)
Suspension Reconstituted ER, Oral, as hydrochloride:
Riomet ER: 500 mg/5 mL (480 mL [DSC]) [contains methylparaben, propylene glycol, propylparaben]
Tablet, Oral, as hydrochloride:
Glucophage: 500 mg [DSC], 850 mg [DSC], 1000 mg [DSC]
Generic: 500 mg, 850 mg, 1000 mg
Tablet Extended Release 24 Hour, Oral, as hydrochloride:
Fortamet: 500 mg [DSC], 1000 mg [DSC]
Glucophage XR: 500 mg [DSC], 750 mg [DSC]
Glumetza: 500 mg, 1000 mg
Generic: 500 mg, 750 mg, 1000 mg
May be product dependent
Extended release tablets utilize differing release mechanisms: Glucophage XR uses dual hydrophilic polymer matrix systems, Fortamet uses single-composition osmotic technology, and Glumetza uses gastric retention technology.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Glucophage: 500 mg, 850 mg
Glycon: 500 mg, 850 mg
Generic: 500 mg, 850 mg
Tablet Extended Release 24 Hour, Oral, as hydrochloride:
Glumetza: 500 mg
Glumetza: 1000 mg [contains fd&c blue #2 (indigotine), fd&c red #40, fd&c yellow #6 (sunset yellow)]
Generic: 500 mg, 1000 mg
Oral: Administer with a meal (to decrease GI upset). Administer Riomet solution and suspension with supplied dosing cup.
ER tablets: Swallow whole; do not crush, cut, or chew. Administer once-daily doses with the evening meal.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablets and oral solution formulations are available.
Fortamet: If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.
Glucophage XR: If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical monitoring is advised given that Glucophage XR is designed to release at a constant rate and peaks approximately 6 hours after administration.
Glumetza: Gastric bypass and sleeve gastrectomy expedite transit of food and water through the remaining stomach. Glumetza is designed to be retained in the stomach and is therefore not advised after gastric bypass or sleeve gastrectomy.
Oral: Administer with a meal (to decrease GI upset).
Immediate release: Glucophage, Riomet: Administer in divided doses with meals. Administer oral solution (eg, Riomet) with supplied dosing cup.
Extended release:
Oral suspension (eg, Riomet ER): Administer with evening meal. Shake well at least 10 seconds before use; use supplied dosing cup to measure dose. Rinse dosing cup with water only after each use to clean.
Tablet (eg, Fortamet, Glucophage XR, Glumetza): Administer once-daily doses with the evening meal; swallow whole; do not cut, crush, or chew; Fortamet should also be administered with a full glass of water.
Diabetes mellitus, type 2: Management of type 2 diabetes mellitus 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 2020).
Antipsychotic-induced weight gain; Diabetes mellitus, type 2 (prevention); Gestational diabetes mellitus (treatment); Polycystic ovary syndrome: Oligomenorrhea due to PCOS (treatment); Polycystic ovary syndrome: Ovarian hyperstimulation syndrome in patients with PCOS undergoing in vitro fertilization/intracytoplasmic sperm injection (prevention)
MetFORMIN may be confused with metroNIDAZOLE
Glucophage may be confused with Glucotrol, Glutofac
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Dianben [Spain] may be confused with Diovan brand name for valsartan [US, Canada, and multiple international markets].
Glucon brand name for metformin [Malaysia, Singapore] is also the brand name for glucosamine [Singapore]
Transient and/or reversible gastrointestinal adverse reactions, including diarrhea, nausea, flatulence, dyspepsia, vomiting, and abdominal pain, among others, are the most commonly reported adverse reactions to metformin use; intolerance to these reactions is often a reason for discontinuation of therapy (Ref).
Mechanism: Dose-related; mechanism not fully understood. Multiple mechanisms have been proposed that may contribute, including alterations in transporters (eg, organic cation transporter 1 [OCT1]), direct serotoninergic-like effects, increased gut motility, direct or indirect increases in glucagon-like peptide 1 (GLP-1), and disruptions in bile (Ref).
Onset: Varied; typically occurs at initiation of therapy; however, late onset of diarrhea has been reported (Ref). Gastrointestinal adverse reactions generally subside after several weeks of therapy; however, some patients require discontinuation.
Risk factors:
• Rapid dose escalation
• Use of IR formulations (Ref)
• Chronic asymptomatic gastritis (Ref)
• Helicobacter pylori infection (Ref)
• Concomitant use of OCT1-inhibiting agents (eg, verapamil, proton pump inhibitors) may be a potential risk factor (Ref)
Postmarketing cases of metformin-associated lactic acidosis (MALA) have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgia, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); and/or increased lactate:pyruvate ratio. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Safety data for use in advanced heart failure (stage D) is lacking (Ref).
Mechanism: Dose-related; inhibition of mitochondrial electron transport, an effect that favors anaerobic metabolism and the accumulation of lactate (Ref), resulting in lactic acidosis without evidence of tissue hypoxia (type B lactic acidosis). In addition, if accumulation occurs (eg, in patients with renal impairment) or if high doses are administered (eg, in overdose), glucose utilization decreases and hepatic production of lactate increases (Ref).
Onset: Varied; may occur at any time during treatment.
Risk factors: In general, risk is increased with increased metformin concentration, decreased lactate clearance, and/or increased lactate production.
• Kidney impairment; risk increases with the severity of kidney impairment
• Hepatic impairment
• Reduced tissue perfusion such as in unstable heart failure (Ref)
• Concomitant use of certain drugs that impair kidney function, cause significant hemodynamic changes, interfere with acid-base balance, or increase metformin accumulation
• Patients ≥65 years of age
• Radiologic study with contrast
• Surgery and other procedures due to potential for volume depletion, hypotension, and renal impairment
• Hypoxic states (eg, acute heart failure, acute myocardial infarction, sepsis, shock)
• Excessive alcohol intake
Long-term use of metformin has been associated with reversible vitamin B12 deficiency and subsequent anemia and neuropathy (Ref).
Mechanism: Time-related; long-term use metformin interferes with the absorption of vitamin B12 (Ref); potential mechanism includes interference of vitamin B12-intrinsic factor absorption in the terminal ileum (Ref).
Onset: Delayed; occurs with chronic use of metformin
Risk factors:
• Duration of therapy
• Inadequate B12 stores, poor underlying nutrition, and inadequate calcium intake or absorption (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Gastrointestinal: Diarrhea (IR tablet: 53% [placebo: 12%]; ER tablet: 10% [placebo: 3%]), flatulence (12% [placebo: 6%]), nausea and vomiting (IR tablet: 26% [placebo 8%]; ER tablet: 7% [placebo: 2%])
1% to 10%:
Cardiovascular: Chest discomfort, flushing, palpitations
Dermatologic: Diaphoresis, nail disease (Lu 2013)
Endocrine & metabolic: Hypoglycemia, vitamin B12 deficiency (7%)
Gastrointestinal: Abdominal distention, abdominal distress (6%), abdominal pain, abnormal stools, dyspepsia (7% [placebo: 4%]), heartburn
Nervous system: Chills, dizziness, headache (6%)
Neuromuscular & skeletal: Asthenia (9%), myalgia
Respiratory: Dyspnea, flu-like symptoms, upper respiratory tract infection
Postmarketing:
Dermatologic: Lichen planus (Azzam 1997)
Endocrine & metabolic: Lactic acidosis (rare: <1%) (DeFronzo 2016; Eppenga 2014; Salpeter 2010)
Hematologic & oncologic: Hemolytic anemia (Packer 2008)
Hepatic: Hepatic injury (cholestatic, hepatocellular, and mixed) (Babich 1998; Nammour 2003)
Hypersensitivity: Fixed drug eruption (Ramírez-Bellver 2017; Steber 2016)
Nervous system: Encephalopathy (Béjot 2015; Jung 2009; Kang 2013)
US labeling: Hypersensitivity to metformin or any component of the formulation; severe renal dysfunction (eGFR <30 mL/minute/1.73 m2); 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; breastfeeding
Disease-related concerns:
• Bariatric surgery: Altered absorption: Use IR tablets or solution after surgery. ER tablets (Glucophage XR [hydrophilic polymer matrix], Fortamet [osmotic technology], Glumetza [gastric-retentive technology]) may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Mechanick 2013; Melissas 2013). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC0-∞ increased by 21%) and bioavailability (increased by 50%) (Padwal 2011). Lactate levels decrease after gastric bypass (RYGB)-induced weight loss irrespective of the use of metformin. Routinely lowering metformin dose after gastric bypass is not necessary as long as normal renal function is preserved (Deden 2018).
• Heart failure: Metformin may be used in patients with stable heart failure (ADA 2020). Use cautiously or avoid in hypoperfusion.
• Hepatic impairment: Use cautiously in patients at risk for lactic acidosis (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; dosing adjustments may be required.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Dosage form specific issues:
• ER tablet: Insoluble tablet shell (Glumetza 1,000 mg tablet) may remain intact and be visible in the stool. Other ER tablets (Fortamet, Glucophage XR, Glumetza 500 mg) may appear in the stool as a soft mass resembling the tablet.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Not indicated for use in patients with type 1 diabetes mellitus or with diabetic ketoacidosis.
• Iodinated contrast: According to the manufacturer, it is recommended to temporarily discontinue 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. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. 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 2020).
• Surgical procedures: Metformin-containing products should be withheld the day of surgery; restart after renal function is stable (ADA 2020).
Substrate of OCT2
Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Risk X: Avoid combination
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Bictegravir: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Risk C: Monitor therapy
Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: 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). Risk D: Consider therapy modification
Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to this combination or use of lower metformin doses. Carefully weigh the risk of metformin toxicities (including lactic acidosis) against the benefit of combining dolutegravir with metformin. Risk D: Consider therapy modification
Erdafitinib: May increase the serum concentration of OCT2 Substrates. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with MATE1/2-K substrates when possible. If combined, monitor for increased MATE1/2-K substrate toxicities. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of fexinidazole with OCT2 substrates when possible. If combined, monitor for increased OCT2 substrate toxicities. Risk D: Consider therapy modification
Fludeoxyglucose F 18: MetFORMIN may diminish the diagnostic effect of Fludeoxyglucose F 18. Management: Consider holding metformin for 48 hours or longer prior to PET scans using fludeoxyglucose F18 (FDG-F18) when imaging of the colon or intestine is required. Consider increased monitoring of blood glucose when metformin is held. Risk D: Consider therapy modification
Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guar Gum (Partially Hydrolyzed): May decrease the serum concentration of MetFORMIN. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. 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. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Risk D: Consider therapy modification
Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Risk C: Monitor therapy
Levoketoconazole: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ondansetron: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Risk D: Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pyrimethamine: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Risk D: Consider therapy modification
Risdiplam: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of risdiplam with MATE substrates if possible. If the combination cannot be avoided, monitor closely for adverse effects. Consider a reduced dose of the MATE substrate according to that substrate's labeling if appropriate. Risk D: Consider therapy modification
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Tafenoquine: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider therapy modification
Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Trilaciclib: May increase the serum concentration of MetFORMIN. Management: Carefully weigh the risk of metformin toxicities (including lactic acidosis) against the benefit of combining trilaciclib with metformin. Consider alternatives to this combination or use of lower metformin doses. Risk D: Consider therapy modification
Trimethoprim: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Vandetanib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Verapamil: May diminish the therapeutic effect of MetFORMIN. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): MetFORMIN may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of MetFORMIN. Risk C: Monitor therapy
Food decreases the extent and slightly delays the absorption. Management: Administer with a meal.
Metformin may increase ovulation in premenopausal anovulatory patients resulting in unintended pregnancies.
Metformin may be used an alternative treatment for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ACOG 201 2018; ADA 2021; Alexopoulos 2019; Egan 2020).
Metformin crosses the placenta; concentrations may be comparable to those found in the maternal plasma (Charles 2006; de Oliveira Baraldi 2011; Eyal 2010; Vanky 2005).
An increased risk of birth defects or adverse fetal/neonatal outcomes has not been observed following maternal use of metformin for gestational diabetes mellitus or type 2 diabetes mellitus when glycemic control is maintained (Balani 2009; Coetzee 1979; Coetzee 1984; Ekpebegh 2007; Niromanesh 2012; Rowan 2008; Rowan 2010; Tertti 2008). However, available guidelines note that long-term safety data are not available (ACOG 190 2018; ACOG 201 2018; ADA 2021).
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia (ACOG 201 2018). 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 (ADA 2021; Blumer 2013).
Pharmacokinetic studies suggest that clearance of metformin may increase during pregnancy and dosing may need adjusted in some patients when used during the third trimester (Charles 2006; Eyal 2010; Gardiner 2003; Hughes 2006; Vanky 2005).
Agents other than metformin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021). Although place in therapy is controversial, metformin may be used as an alternative agent in some patients requiring therapy for gestational diabetes mellitus or type 2 diabetes mellitus; studies in pregnancy are ongoing (ACOG 190 2018; ACOG 201 2018; ADA 2021; Alexopoulos 2019; Egan 2020).
Metformin is present in breast milk.
The relative infant dose (RID) of metformin is 1.08% when calculated using the highest average breast milk concentration located and compared to a weight-adjusted maternal dose of 6.55 mg/kg/day.
In general, breastfeeding is considered acceptable when the RID is <10 (Anderson 2016; Ito 2000).
The RID of metformin was calculated using a milk concentration of 0.47 mcg/mL, providing an estimated daily infant dose via breast milk of 0.07 mg/kg/day. This milk concentration was obtained following maternal administration of metformin 500 mg twice daily and the RID was calculated using the actual weight of the woman in the study (Briggs 2005).
Small amounts of metformin have been detected in the serum of breastfeeding infants. Because breast milk concentrations of metformin stay relatively constant, avoiding breastfeeding around peak plasma concentrations in the mother would not be helpful in reducing metformin exposure to the infant (Briggs 2005; Eyal 2010; Gardiner 2003; Hale 2002).
Appropriate glycemic control is required for the establishment of lactation in patients with diabetes mellitus (Anderson 2018). Breastfeeding provides metabolic benefits to mothers with diabetes mellitus as well as their infants; therefore, breastfeeding is encouraged (ACOG 201 2018; ADA 2021; Blumer 2013). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Metformin may be used in patients who are breastfeeding (Blumer 2013).
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.
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 in whom treatment goals have not been met, or with therapy change [ADA 2020]). Initial and annual monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices); renal function (eGFR) prior to therapy initiation and at least annually (more often in patients at risk of developing renal impairment; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m2; every 3 months if eGFR 30 to <45 mL/minute/1.73 m2 [Lipska 2011]). Monitor vitamin B12 serum concentrations every 2 to 3 years (in particular those with peripheral neuropathy or anemia); folate (if megaloblastic anemia is suspected).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults with diabetes (ADA 2020):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics).
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2020):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (eg, sulfonylureas) (LeRoith 2019).
HbA1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment).
Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Pregnant patients:
HbA1c: Pregestational diabetes (type 1 or type 2) (ADA 2020):
Preconception (patients planning for pregnancy): <6.5%.
During pregnancy: <6% (if can be achieved without significant hypoglycemia) or <7% (if needed to prevent hypoglycemia).
Capillary blood glucose: Pregestational diabetes mellitus (type 1 or type 2) (ADA 2020) or gestational diabetes mellitus (ACOG 190 2018) (less stringent targets may be appropriate if goals cannot be achieved without causing significant hypoglycemia): Fasting: <95 mg/dL. Postprandial: <140 mg/dL (at 1 hour) or <120 mg/dL (at 2 hours).
Pediatric (all age groups) patients with diabetes (ADA 2020):
Preprandial glucose: 70 to 130 mg/dL (ISPAD [Dimeglio 2018]).
Postprandial glucose: 90 to 180 mg/dL (ISPAD [Dimeglio 2018]).
Bedtime/overnight glucose: 80 to 140 mg/dL (ISPAD [Dimeglio 2018]).
HbA1c: <7%; target should be individualized; a more stringent goal (<6.5%) may be reasonable if it can be achieved without significant hypoglycemia; less aggressive goals (<7.5% or <8%) may be appropriate in patients who cannot articulate symptoms of hypoglycemia, cannot check glucose frequently, have a history of severe hypoglycemia, or have extensive comorbid conditions (ADA 2020; ISPAD [Dimeglio 2018]).
Surgical patients (ISPAD [Jefferies 2018]):
Intraoperative: 90 to 180 mg/dL.
ICU, postsurgery: 140 to 180 mg/dL.
Classification of hypoglycemia (ADA 2020):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)
Onset of action: Within days; maximum effects up to 2 weeks.
Distribution: Vd: 654 ± 358 L; partitions into erythrocytes; concentrates in liver, kidney, and GI tract.
Protein binding: Negligible.
Metabolism: Not metabolized by the liver.
Bioavailability: Absolute: Fasting: 50% to 60%.
Half-life elimination: Plasma: 4 to 9 hours; Blood ~17.6 hours.
Time to peak, serum: Immediate release: 2 to 3 hours; ER tablet: 7 hours (range: 4 to 8 hours); ER suspension: 4.5 hours (range: 3.5 to 6.5 hours).
Excretion: Urine (90% as unchanged drug; active secretion).
Renal function impairment: Peak and systemic exposure is increased, and oral and renal clearance is decreased.
Pediatric: Obesity: In 22 pediatric patients who were obese (mean age: 14.5 ± 1.8 years; range: 11.1 to 17.5 years), pharmacokinetic analysis showed that clearance significantly increases and AUC decreases with increasing total body weight (van Rongen 2018).
Geriatric: Total plasma clearance is decreased, half-life is prolonged, and Cmax is increased.
Solution (metFORMIN HCl Oral)
500 mg/5 mL (per mL): $1.35
Solution (Riomet Oral)
500 mg/5 mL (per mL): $1.69
Tablet, 24-hour (Glumetza Oral)
500 mg (per each): $61.78
1000 mg (per each): $133.60
Tablet, 24-hour (metFORMIN HCl ER (MOD) Oral)
500 mg (per each): $8.40 - $55.99
1000 mg (per each): $16.67 - $126.20
Tablet, 24-hour (metFORMIN HCl ER (OSM) Oral)
500 mg (per each): $4.52 - $17.24
1000 mg (per each): $6.38 - $31.40
Tablet, 24-hour (metFORMIN HCl ER Oral)
500 mg (per each): $0.75 - $1.08
750 mg (per each): $1.20 - $1.61
Tablets (metFORMIN HCl Oral)
500 mg (per each): $0.03 - $0.70
850 mg (per each): $0.06 - $1.20
1000 mg (per each): $0.07 - $1.45
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