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Repaglinide and metformin: Drug information

Repaglinide and metformin: Drug information
(For additional information see "Repaglinide and metformin: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Lactic acidosis:

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), an 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), age 65 years and older, 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 repaglinide/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Pharmacologic Category
  • Antidiabetic Agent, Biguanide;
  • Antidiabetic Agent, Meglitinide Analog
Dosing: Adult
Diabetes mellitus, type 2, treatment

Diabetes mellitus, type 2, treatment: Note: Daily doses should be divided and given 2 to 3 times daily with meals; Maximum single dose: Repaglinide 4 mg/metformin 1,000 mg; Maximum daily dose: Repaglinide 10 mg/metformin 2,500 mg/day.

Patients currently taking repaglinide and metformin: Oral: Initial doses should be based on (but not exceed) the patient's current doses of repaglinide and metformin; titrate as needed to the maximum daily dose to achieve targeted glycemic control.

Patients inadequately controlled with metformin monotherapy: Oral: Initial: Repaglinide 1 mg/metformin 500 mg twice daily with meals. Titrate slowly to reduce the risk of repaglinide-induced hypoglycemia.

Patients inadequately controlled with glinide monotherapy: Oral: Initial: Metformin 500 mg twice daily plus repaglinide at a dose similar to (but not exceeding) the patient's current dose. Titrate slowly to reduce the risk of metformin-induced gastrointestinal adverse effects.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

eGFR >45 mL/minute/1.73 m2: No dosage adjustment necessary

eGFR 30 to 45 mL/minute/1.73 m2:

Preexisting impairment: Use of repaglinide/metformin is not recommended for initiation of therapy. Refer also to individual agents.

If eGFR falls between 30 to <45 mL/minute/1.73 m2 during therapy: Consider benefits/risks of continuing therapy. If continuing metformin therapy, a dosage reduction of 50% (maximum: Metformin 1,000 mg/day) and monitoring of renal function every 3 months is recommended (ADA [Lipska 2011]; Inzucchi 2014).

eGFR <30 mL/minute/1.73m2: Use is contraindicated

Dosing: Hepatic Impairment: Adult

The manufacturer recommends avoiding metformin because 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 chronic liver disease with impaired hepatic function 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). Repaglinide should be used with caution in patients with hepatic impairment.

Dosing: Older Adult

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. The following information reflects the frequency of adverse effects experienced by patients who received the repaglinide/metformin fixed-dose combination product. Also see individual agents.

>10%:

Central nervous system: Headache (22%)

Endocrine & metabolic: Hypoglycemia (33%)

Gastrointestinal: Diarrhea (19%), nausea (15%)

Respiratory: Upper respiratory tract infection (11%)

Contraindications

Hypersensitivity to repaglinide, metformin, or any component of the formulation; severe renal impairment (GFR <30 mL/min/1.73 m2); acute or chronic metabolic acidosis (including diabetic ketoacidosis); concomitant administration of gemfibrozil.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Use in combination with NPH insulin is not indicated; in 2 studies, reports of myocardial ischemia (6 events) in patients using repaglinide plus insulin have caused concern. Further evaluation is required to assess the safety of this combination.

• Hypoglycemia: Severe hypoglycemia may occur with repaglinide; risk may be increased by changes in meal patterns, changes in physical activity levels, changes to coadministered medications, concomitant use with other antidiabetic agents. Symptoms may be less pronounced in patients with longstanding diabetes, diabetic neuropathy, recurrent hypoglycemia or taking concurrent medications blocking the sympathetic nervous system. Monitor blood glucose more frequently in patients at high risk of hypoglycemia or who may have reduced symptomatic awareness of hypoglycemia.

• Lactic acidosis: 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: Long-term metformin use is associated with vitamin B12 deficiency.

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Use immediate-release tablets after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Mingrone 2016). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of immediate-release 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).

– Hypoglycemia: May increase the risk of hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period after surgery. Where possible, the selection of antidiabetic agents without the potential for hypoglycemia is advised.

• Heart failure: Metformin may be used in patients with stable heart failure; use cautiously or avoid in hypoperfusion (ADA 2023).

• Hepatic impairment: Use metformin cautiously in patients at risk for lactic acidosis (Brackett 2010; Crowley 2017; Zhang 2014).

• Renal impairment: Risk of hypoglycemia may be increased in patients with renal impairment. Metformin is substantially excreted by the kidney; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. 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 therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Special populations:

• Older adult: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis or type 1 diabetes mellitus.

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: Administration of iodinated contrast agents has been associated with post-contrast acute kidney injury; in patients taking metformin, acute decreases in renal function have been associated with an increased risk of lactic acidosis due to reduced metformin excretion (ACR 2021; manufacturer's labeling). Refer to metformin monograph for additional information.

• Surgical procedures: Metformin-containing products should be withheld the day of surgery; restart after renal function is stable (ADA 2023).

Dosage Forms: US

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

Tablet, Oral:

Generic:

1/500: Repaglinide 1 mg and metformin hydrochloride 500 mg [DSC]

2/500: Repaglinide 2 mg and metformin hydrochloride 500 mg [DSC]

Generic Equivalent Available: US

Yes

Pricing: US

Tablets (Repaglinide-metFORMIN HCl Oral)

1-500 mg (per each): $6.14

2-500 mg (per each): $6.14

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Administer up to 30 minutes before meals to avoid risk of hypoglycemia/GI upset; if a meal is skipped or patient is unable to take anything by mouth, do not administer dose.

Use: Labeled Indications

Diabetes mellitus, type 2, treatment: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Medication Safety Issues
Sound-alike/look-alike issues:

PrandiMet may be confused with Avandamet, Prandin

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, excessive alcohol ingestion (acute or chronic) may potentiate the risk of lactic acidosis. Risk X: Avoid combination

Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

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

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Asciminib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. 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

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Clopidogrel: May increase the serum concentration of Repaglinide. Management: Avoid use of clopidogrel and repaglinide if possible; if the combination must be used, limit total repaglinide daily dose to no more than 4 mg. This is contraindicated in some non-US labeling. Risk D: Consider therapy modification

CycloSPORINE (Systemic): May increase the serum concentration of Repaglinide. Management: Limit the daily repaglinide dose to a maximum of 6 mg with concurrent use of cyclosporine, and monitor closely for increased repaglinide effects. Risk D: Consider therapy modification

CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Risk X: Avoid combination

CYP2C8 Inhibitors (Weak): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy

Darolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). 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

Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Encorafenib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Consider alternatives to this combination when possible. If combined, monitor for increased effects/toxicities of OCT2 substrates and consider OCT2 substrate dose reductions when appropriate. Risk D: Consider therapy modification

Erythromycin (Systemic): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy

Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

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

Foslevodopa: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gilteritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Meglitinides. Management: Consider meglitinide dose reductions when used in combination with glucagon-like peptide-1 agonists, particularly when also used with basal insulin. 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

Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

HMG-CoA Reductase Inhibitors (Statins): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy

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

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated 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

Irbesartan: May increase the serum concentration of Repaglinide. 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

Lapatinib: May increase the serum concentration of CYP2C8 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Leflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Leniolisib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Letermovir: May increase the serum concentration of Repaglinide. Management: Monitor for increased repaglinide effects/toxicities (ie, hypoglycemia) if combined with letermovir. When letermovir is coadministered with cyclosporine, the use of repaglinide is not recommended. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

MATE1/2-K Inhibitors: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

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

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). 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

Pacritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

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

Pretomanid: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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

RifAMPin: May decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

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

Spironolactone: May increase the serum concentration of CYP2C8 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). 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 (Clinically Relevant with Inhibitors). 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

Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Taurursodiol: May increase the serum concentration of CYP2C8 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination

Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

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. Specifically, the risk for lactic acidosis may be increased. MetFORMIN may increase the serum concentration of Topiramate. Topiramate may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Trofinetide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider therapy modification

Tucatinib: May increase the serum concentration of Repaglinide. 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

Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Food Interactions

See individual agents.

Reproductive Considerations

Metformin may increase ovulation in premenopausal anovulatory patients resulting in unintended pregnancies.

Refer to individual monographs for additional information.

Pregnancy Considerations

Metformin crosses the placenta (ADA 2023).

Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.

Breastfeeding Considerations

Metformin is present in breast milk; the presence of repaglinide is not known.

Due to the potential for hypoglycemia in a breastfeeding infant, breastfeeding is not recommended by the manufacturer.

Refer to individual monographs for additional information.

Dietary Considerations

Individualized medical nutrition therapy based on ADA recommendations is an integral part of therapy.

Monitoring Parameters

Plasma glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors) (ADA 2023) Monitor renal function (eGFR) prior to therapy initiation and at least annually or at least every 3 to 6 months if eGFR is <60 mL/minute/1.73 m2 (KDIGO 2020). Monitor hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) annually; folate if megaloblastic anemia is suspected. Monitor vitamin B12 serum concentrations every 1 to 2 years, particularly in patients who have been treated with metformin for ≥4 years, or in patients with peripheral neuropathy, anemia, or risk factors for vitamin B12 deficiency (eg, malabsorption syndromes, reduced dietary intake) (ADA 2023; KDIGO 2020; manufacturer's labeling).

HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2023; KDIGO 2020).

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (AACE [Samson 2023]; ADA 2023):

HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note : In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.

Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).

Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).

Older adults (≥65 years of age) (ADA 2023):

Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (eg, sulfonylureas, meglitinides) (ES [LeRoith 2019]).

HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.

Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).

Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).

Classification of hypoglycemia (ADA 2023):

Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.

Level 2: <54 mg/dL (SI: <3 mmol/L); 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.

Mechanism of Action

Combination therapy; repaglinide and metformin act to improve glycemic control via two different mechanisms of action:

Repaglinide is a nonsulfonylurea hypoglycemic agent which stimulates insulin release by blocking ATP-dependent potassium channels, depolarizing the membrane and facilitating calcium entry through calcium channels; increased intracellular calcium stimulates insulin release from the pancreatic beta cells.

Metformin prevents hyperglycemia by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity via increased peripheral glucose uptake and utilization.

Pharmacokinetics (Adult Data Unless Noted)

See individual agents.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (CI) Côte d'Ivoire: Nidiadem;
  • (CN) China: Repaglinide and metformin hydrochloride tablets (i) | Repaglinide and metformin hydrochloride tablets (ii);
  • (EG) Egypt: Replitza;
  • (IN) India: Eurepa mf;
  • (MX) Mexico: Blinotin;
  • (PR) Puerto Rico: Repaglinide and metformin hydrochloride;
  • (TR) Turkey: Pareglin;
  • (TW) Taiwan: Repass
  1. American College of Radiology Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. https://www.acr.org/Clinical-Resources/Contrast-Manual. Published January 2021. Accessed July 13, 2021.
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