Drug class: Meglitinides

Medically reviewed by Drugs.com on Apr 10, 2025. Written by ASHP.

Introduction

Antidiabetic agent; meglitinide (glinide) derivative.^{2 6 8 11 12 56 57 59 60 61 63 65}

Uses for Repaglinide

Type 2 Diabetes Mellitus

Glycemic Control

Used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{1 61 65}

Used as monotherapy or in combination with other antidiabetic agents (e.g., metformin, thiazolidinediones).^{2 12 13 58 59 60 61 64 67 68 80 81 102 114}

Guidelines from the American Diabetes Association (ADA) and other experts generally recommend that meglitinide (including repaglinide) use be limited or discontinued due to lack of additive beneficial effect on cardiovascular and renal comorbidities and increased risk of hypoglycemia and weight gain.^{707 708} Some experts state that meglitinides may be a treatment option in patients with access or cost barriers to other preferred antidiabetic agents.⁷⁰⁸ When selecting a treatment regimen, consider factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences.^{707 708} Weight management should be included as a distinct treatment goal, and other healthy lifestyle behaviors should also be considered.^{707 708}

Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.^{1 61}

Repaglinide Dosage and Administration

General

Pretreatment Screening

• Fasting and postprandial blood glucose determinations should be performed to determine therapeutic response and the minimum effective dosage.¹

Patient Monitoring

• Monitor patients with regular laboratory evaluations, including fasting blood glucose determinations, to assess therapeutic response and minimum effective dosage.^{1 707 708}

• During dosage titration, obtain fasting and postprandial blood glucose concentrations weekly to determine therapeutic response and minimum effective dosage of repaglinide; thereafter, monitor HbA_1c values approximately every 3 months to evaluate long-term glycemic control.^{1 707 708}

• Patients should perform self-monitoring of blood glucose.¹ In patients at higher risk for hypoglycemia and in those with reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.¹

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) includes and repaglinide and rasagiline on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these drugs.⁷⁰⁹

Administration

Administer orally.¹

Instruct patients to take within 30 minutes before meals.¹ Depending on meal patterns, administer 2—4 times daily.^{1 59 61} Administration with food may affect extent of absorption.⁵⁹

If a meal is skipped or added, skip or add a dose, respectively, for that meal.^{1 59 61 62 68}

Dosage

Adults

Type 2 Diabetes Mellitus

Repaglinide

Oral

Patients with HbA_1c <8%: Initially, 0.5 mg (minimum effective dosage) preprandially 2–4 times daily (depending on meal patterns).¹

Patients with HbA_1c ≥8%: Initially, 1 or 2 mg preceding each meal.¹

Subsequent dosage should be adjusted according to therapeutic response and tolerance, using lowest possible effective dosage.¹ May double dosage at no less than weekly intervals until satisfactory glycemic control achieved or maximum daily dosage of 16 mg (e.g., 4 mg four times daily depending on meal patterns) is attained.¹ Reduce dosage in patients that experience hypoglycemia.¹

Dosage Modification for Drug Interactions

Concomitant administration of repaglinide and strong CYP2C8 or CYP3A4 inhibitors or inducers may require dosage adjustments; concomitant repaglinide and gemfibrozil contraindicated.¹

Avoid concomitant repaglinide and clopidogrel; if unable to avoid concomitant use, limit initial repaglinide dosage to 0.5 mg preprandially and do not exceed total daily dosage of 4 mg.¹

With concomitant cyclosporine, do not exceed total daily repaglinide dosage of 6 mg.¹

Special Populations

Hepatic Impairment

Use with caution.¹ Manufacturer recommends same initial dosage used in patients with normal hepatic function, but should make subsequent dosage adjustments at longer than usual intervals (e.g., 3 months) to allow full assessment of response.¹

Renal Impairment

Mild to moderate renal impairment (Cl_cr 40—80 mL/minute): No adjustment in initial dosage necessary.¹

Severe renal impairment (e.g., Cl_cr 20–40 mL/minute): Initiate dosage of 0.5 mg daily and titrate carefully.¹

Use not established in patients with Cl_cr <20 mL/minute or those with renal failure requiring hemodialysis.¹

Geriatric Patients

No dosage adjustment necessary based solely on age; greater sensitivity to hypoglycemia cannot be ruled out.^{1 101}

Cautions for Repaglinide

Contraindications

• Concomitant use of gemfibrozil.¹

• Known hypersensitivity to repaglinide or any ingredient in the formulation.¹

Warnings/Precautions

Hypoglycemia

Potential for hypoglycemia.^{1 80 81 99 100 101 102 104 105} Severe hypoglycemia can cause seizures, may be life-threatening, or cause death.¹

Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient.¹ Symptomatic awareness of hypoglycemia may be less pronounced in those with longstanding diabetes, with diabetic nerve disease, in those using medications that block the sympathetic nervous system (e.g., ß-blocking agents), or in those who experience recurrent hypoglycemia.¹

Factors that may increase risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in physical activity level, changes to coadministered drugs, and concomitant use of other antidiabetic agents.¹

Patients should administer repaglinide before meals and be instructed to skip the dose if a meal is skipped.¹ Reduce dosage in patients that experience hypoglycemia.¹ Educate patients and caregivers to recognize and manage hypoglycemia.¹ Self-monitoring plays essential role in prevention and management.¹ In patients at higher risk of hypoglycemia and/or with reduced symptomatic awareness, increased frequency of blood glucose monitoring recommended.¹

Serious Cardiovascular Adverse Reactions with Concomitant Use of Isophane (NPH) Insulin

Myocardial ischemia was observed in a few patients receiving repaglinide in combination with NPH insulin in clinical trials, and manufacturer states that repaglinide is not indicated for use in combination with NPH insulin.¹

Macrovascular Outcomes

Manufacturer states that there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide.¹

Specific Populations

Pregnancy

Limited data suggest no apparent drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with repaglinide use during pregnancy.¹ Poorly controlled diabetes mellitus during pregnancy carries risks to mother and fetus.¹

Lactation

No data on presence of repaglinide in human milk, effects on breast-fed infant, or effects on milk production.¹ Distributed into milk in rats.¹

Not recommended for use when breastfeeding due to risk of hypoglycemia in breast-fed infants.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Safety and efficacy appear to be similar in geriatric and younger patients except for the expected age-related increase in cardiovascular morbidity observed with repaglinide and other comparative oral antidiabetic agents.^{1 101} No increase in frequency and severity of hypoglycemia in geriatric versus younger patients receiving repaglinide.^{1 101}

Hepatic Impairment

Since repaglinide is eliminated principally by the liver, patients with hepatic impairment have greater systemic exposure.¹ Use with caution.^{1 59}

Renal Impairment

Renal impairment is associated with increases in plasma concentrations of repaglinide.¹ Use with caution.^{1 61}

Common Adverse Effects

Most common adverse effects (≥5%): hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, back pain.¹

Drug Interactions

Metabolized by CYP3A4 and CYP2C8 to inactive metabolites.¹

Appears to be a substrate for organic anion-transporting protein (OATP) 1B1.^{1 200}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 or CYP2C8: Potential pharmacokinetic interaction (increased repaglinide AUC and peak plasma concentrations).¹ Close monitoring of blood glucose concentrations suggested; dosage adjustment of repaglinide may be necessary.^{1 59}

Inducers of CYP3A4 or CYP2C8: Potential pharmacokinetic interaction (decreased repaglinide AUC and peak plasma concentrations).^{1 59 62 64} Close monitoring of blood glucose concentrations suggested; dosage adjustment of repaglinide may be necessary.^{1 59}

Drugs Affecting or Affected by Transport Systems

OATP 1B1 inhibitors: Potential pharmacokinetic interaction (increased repaglinide concentrations).¹

Protein-bound Drugs

Potential pharmacokinetic interaction with other protein-bound drugs (increased free repaglinide concentrations due to displacement from plasma protein binding sites by other drugs).^{1 61 64 104} Conversely, repaglinide could displace other protein-bound drugs from binding sites.¹

Repaglinide Pharmacokinetics

Absorption

Bioavailability

Approximately 56%.^{1 61}

Peak plasma drug concentrations attained within approximately 1 hour.^{1 10 56 59 60 61 62 64 65 68 100 107}

Onset

Peak serum insulin concentrations achieved in approximately 1.5 hours.¹¹³

Maximum glycemic effect within 3–3.5 hours.^{2 61 79}

Duration

Plasma insulin concentrations increase in proportion to dose and return toward premeal concentrations between meals and at bedtime.^{1 2 11 61 64}

Food

Food may delay and reduce the extent of GI absorption.^{1 59 61} Administration with a high-fat meal slightly reduces peak plasma concentration and AUC but not time to peak concentration;^{60 61 64} reduction not clinically important.^{1 59}

Special Populations

Greater systemic exposure (as determined by peak plasma concentrations and AUCs) to repaglinide in patients with hepatic impairment.^{1 61 105}

Increases in plasma concentrations and AUC of repaglinide in patients with severe renal impairment (Cl_cr 20–40 mL/minute).^{1 59 60 61 64 104} Such alterations not found in patients with mild to moderate renal impairment (Cl_cr 40—80 mL/minute).^{1 104}

No pharmacokinetic differences (peak plasma concentration, AUC) observed in geriatric individuals (≥65 years of age) compared with healthy younger individuals.^{1 101}

Distribution

Extent

Distributes into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

>98%.^{1 61 64 104}

Elimination

Metabolism

Rapidly metabolized by CYP3A4 and CYP2C8 to inactive metabolites.^{1 59 62 64 65 67 80 81 99 100 101 104 105 107}

Elimination Route

Extensively metabolized in liver and excreted into feces (90%) as metabolites.^{1 3 56 59 60 61 64 68 80 99 104 106 107}

Small amount excreted in urine (8%) principally as metabolites.^{1 56 59 60 61 64 65 68 80 99 104 106 107}

Half-life

About 1 hour.^{1 3 59 61 62 64 65 68 101 107}

Special Populations

In patients with hepatic impairment, elimination of unbound repaglinide reduced compared with that in healthy individuals.^{1 105}

Stability

Storage

Oral

Tablets

Store at 20—25°C.¹ Keep bottle tightly closed; protect from moisture.¹

Actions

• Does not stimulate insulin release in the absence of glucose; insulin release diminished at low glucose concentrations.^{2 7 9 60 64}

• As blood glucose concentrations increase, augments the glucose-induced closure of ATP-sensitive potassium channels and, thereby, the release of insulin.^{8 9 58 59 60 61 63}

• Exerts most of its insulinotropic activity at intermediate glucose concentrations (54–180 mg/dL).^{9 60 63} At high glucose concentrations (>270 mg/dL), does not augment the insulin release already stimulated by high extracellular glucose concentrations.^{9 60 63}

• Effect on potassium and calcium channels is somewhat selective for pancreatic β-cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.^{1 80}

• As with sulfonylurea antidiabetic agents, requires functioning pancreatic β-cells for hypoglycemic activity, since the drug lowers blood glucose concentrations principally by augmenting endogenous insulin secretion from the pancreas in response to a meal.^{1 56 57 58 59 60 61 62 64 67}

• Weight gain observed in therapy-naive patients.^{1 56 64 80 100} Suggested mechanisms for increased weight include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or resistance to the actions of leptin (which decreases appetite and increases energy expenditure).^{13 50 56 74 111 112}

Advice to Patients

• Inform patients of the potential risks and advantages of repaglinide therapy and of alternative forms of treatment.¹

• Instruct patients to take repaglinide within 30 minutes before meals.¹ Inform patients to skip the dose of repaglinide if a meal is skipped.¹

• To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of repaglinide and administration of insulin may be required.^{1 61} According to the clinician’s judgment, repaglinide therapy may be reinstituted after the acute episode is resolved.^{1 61}

• Inform patients and caregivers of the signs, symptoms, and management of hypoglycemia.¹ Inform patients that their ability to concentrate and react may be impacted as a result of hypoglycemia.¹ Inform patients that self-monitoring of blood glucose is essential in the prevention and management of hypoglycemia.¹ Inform patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia that increased frequency of blood glucose monitoring is recommended.¹

• Inform patients receiving repaglinide that monitoring with regular laboratory evaluations, including blood glucose determinations, is needed to determine the minimum effective dosage of repaglinide when used either as monotherapy or in combination with other antidiabetic agents.¹ Inform patients that glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements also are useful, particularly for monitoring long-term control of blood glucose concentration.¹

• Advise patients of the importance of adherence to dietary instructions, regular physical activity, and assessment of diabetes mellitus complications.^{707 708}

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.¹ Inform patients that because of the potential for repaglinide to cause hypoglycemia in breast-fed infants, repaglinide is not recommended for use when breastfeeding.¹

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Inform patients of other important precautionary information.¹

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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