Repaglinide

Class: Meglitinides
ATC Class: A10BX02
VA Class: HS502
Chemical Name: (S)-2-Ethoxy-4-[2-[[methyl-1-[2-(1-piperidinyl)-phenyl]butyl]amino]-2-oxoethyl]-benzoic acid
CAS Number: 135062-02-1
Brands: Prandin

Introduction

Antidiabetic agent; meglitinide derivative.^{2 6 8 11 12 14 56 57 59 60 61 63 65}

Uses for Repaglinide

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in patients whose hyperglycemia cannot be controlled by diet and exercise alone.^{1 5 61 65}

Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.^{24 25 56 76}

May be used in combination with metformin or a thiazolidinedione antidiabetic agent (e.g., pioglitazone, rosiglitazone) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent.^{1 5 13 59 61 102}

Has been used in combination with isophane (NPH) insulin† to improve glycemic control in patients with type 2 diabetes mellitus who do not respond adequately to therapy with one or more oral antidiabetic agents.^{56 115}

Repaglinide Dosage and Administration

General

• 
  

  Carefully individualize dosage based on patient response and tolerance.^{1 71 81 99}

  
  


• 
  

  Goal of therapy is to reduce both fasting blood (or plasma) glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) values to normal or near normal using lowest effective dosage of repaglinide, either when used as monotherapy or in combination with metformin or a thiazolidinedione.^{1 14 71 99}

  
  


• 
  

  (Glucose concentrations in plasma generally are 10–15% higher than those in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations.)^{31 51}

  
  


• 
  

  Monitor patients with regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess therapeutic response and minimum effective dosage.^{1 14 31 109} American Diabetes Association (ADA) and some clinicians currently suggest that routine blood glucose monitoring should include fasting and 2-hour postprandial blood glucose concentrations.^{40 71 109}

  
  


• 
  

  May be helpful to determine postprandial blood glucose concentrations in patients whose preprandial blood glucose concentrations are satisfactory but whose overall glycemic control (as determined by glycosylated hemoglobin values) is inadequate.¹ Monitoring of glucose concentrations may be useful to detect primary failure (inadequate lowering of glucose concentration at maximum recommended dosage) or secondary failure (loss of glycemic control following an initial period of effectiveness) of drug therapy.^{1 14 71}

  
  


• 
  

  During initiation of therapy and titration of dosage, perform fasting and postprandial blood glucose determinations weekly to determine therapeutic response and minimum effective dosage of repaglinide; thereafter, glycosylated hemoglobin values should be monitored approximately every 3 months to evaluate long-term glycemic control.^{1 5 14 31 40 71} In patients usually well controlled by dietary management alone, short-term therapy with repaglinide may be sufficient during periods of transient loss of diabetic control.^{1 5 14}

  
  


• 
  

  If inadequate glycemic control and/or secondary failure occurs during maintenance therapy with repaglinide, a sulfonylurea, a thiazolidinedione, or metformin alone, combined therapy with metformin or a thiazolidinedione and repaglinide may result in an adequate response.^{1 14 102} If secondary failure occurs with combined metformin and repaglinide therapy, most clinicians currently recommend discontinuance of oral antidiabetic agents and initiation of insulin therapy.^{1 14 40} However, other options include the addition of a third oral antidiabetic agent (e.g., acarbose, a thiazolidinedione) before switching to insulin therapy.^{40 56 59 71} (See Diabetes Mellitus under Uses.)

  
  

Transferring from Therapy with Other Antidiabetic Agents

• 
  

  Transition period generally not required when transferring from most other oral antidiabetic agents; may abruptly discontinue other oral antidiabetic agent and initiate repaglinide the day after the final dose of that drug.^{1 5 14}

  
  


• 
  

  Exaggerated hypoglycemic response may occur in some patients during transition from a long-acting sulfonylurea antidiabetic agent (e.g., chlorpropamide) to repaglinide; may be necessary to monitor closely for hypoglycemia for one week or longer after transition.^{1 5 14 61 71}

  
  

Concomitant Therapy with Metformin or a Thiazolidinedione

• 
  

  If adequate glycemic control (i.e., fasting blood glucose concentrations between 80 and 140 mg/dL with infrequent hypoglycemic episodes) not achieved with repaglinide monotherapy,^{14 31 111} may add metformin or a thiazolidinedione.^{1 14 27 31 36 71} May also use in combination with metformin and thiazolidinedione in patients who have inadequate glycemic control after 2–3 months with initial metformin, sulfonylurea, or thiazolidinedione monotherapy.^{1 14 27 31 36 40 102 109}

  
  


• 
  

  Titrate initial dosage of repaglinide during combination therapy as with repaglinide monotherapy.^{1 14} With concomitant metformin or thiazolidinedione and repaglinide therapy, adjust dosage of each drug to obtain adequate glycemic control (as determined by fasting plasma glucose and glycosylated hemoglobin concentrations) using minimum effective dosage of each drug.^{1 14} Failure to titrate the dosage of each drug to the minimum effective level could result in an increased risk of hypoglycemic episodes.^{1 14 71}

  
  


• 
  

  In patients who do not respond to 3 months of concomitant therapy at the maximum dosage of each oral antidiabetic agent, generally should discontinue therapy with oral antidiabetic agents and institute insulin therapy.^{1 14 27} Other options include adding a third oral antidiabetic agent (e.g., acarbose, a thiazolidinedione) before switching to insulin therapy.^{1 14 27 40 56 59 71} (See Diabetes Mellitus under Uses.)

  
  

Administration

Oral Administration

Generally, administer within 15 minutes of each meal but may give as early as 30 minutes prior to each meal up to immediately preceding each meal.^{1 59 61 71} Administration with food may affect the extent of absorption.^{14 59} (See Food under Pharmacokinetics.)

Pre-meal doses may enhance glycemic control compared with twice-daily dosing at breakfast and dinner using the same total daily dosage.^{11 71}

If a meal is skipped or added, skip or add a dose, respectively, for that meal.^{1 5 14 59 61 62 68 71}

Dosage

Adults

Diabetes Mellitus

Oral

Initially, 0.5 mg (the minimum effective dosage) preprandially 2–4 times daily (depending on meal patterns) in patients not previously treated with oral antidiabetic agents or in those who have relatively good glycemic control (i.e., glycosylated hemoglobin <8%).^{1 5 14 40 56 61 62 71}

Patients with glycosylated hemoglobin ≥8% despite treatment with other oral antidiabetic agents: initially, 1 or 2 mg with or preceding each meal.^{1 5 14 61 62 71}

Approximately 90% of maximal glucose-lowering effect is achieved with dosage of 1 mg 3 times daily.^{56 57 66}

May double dosage at no less than weekly intervals until desired fasting blood glucose concentration (e.g., 80–140 mg/dL with infrequent hypoglycemic episodes) is achieved or maximum daily dosage of 16 mg (e.g., 4 mg four times daily depending on meal patterns) is attained.^{1 3 5 14 27 31 36 56 59 61 62 71}

Safety and efficacy of higher dosages (8–20 mg 3–4 times daily before meals) not established.^{14 71}

Prescribing Limits

Adults

Diabetes Mellitus

Oral

Maximum daily dosage of 16 mg (e.g., 4 mg four times daily depending on meal patterns) recommended by manufacturer;^{1 3 5 14 27 31 36 56 59 61 62 71} higher dosages have been used.^{14 71} (See Diabetes Mellitus under Dosage and Administration.)

Special Populations

Renal Impairment

Mild to moderate renal dysfunction: No adjustment in initial dosage necessary.¹ May administer usual initial dosage but use caution with subsequent dosage increases.^{1 5 59 61 71 104}

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

Hepatic Impairment

Use with caution.^{1 5 59 71} 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 5 59 61 71 105} Some clinicians suggest lower initial dosage in patients with hepatic impairment.⁶⁴

Cautions for Repaglinide

Contraindications

• 
  

  Sole therapy in patients with type 1 (insulin-dependent) diabetes mellitus or in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.^{1 5 61 71}

  
  


• 
  

  Known hypersensitivity to repaglinide or any ingredient in the formulation.^{1 61}

  
  

Warnings/Precautions

General Precautions

Hypoglycemia

Potential for hypoglycemia.^{1 5 14 80 81 99 100 101 102 104 105} Debilitated, malnourished, or geriatric patients and those with hepatic or severe renal impairment or adrenal or pituitary insufficiency may be particularly susceptible.^{1 5 61} Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.^{1 5 61 71}

Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.^{1 5} Increased risk of serious hypoglycemia in patients with hepatic failure, who may have reduced clearance of repaglinide and diminished gluconeogenic capacity.^{1 5 61 64}

Appropriate patient selection, patient education, and careful attention to dosage are important to avoid hypoglycemic episodes.¹

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).^{1 31 61 71} Temporary discontinuance of repaglinide and administration of insulin may be required.^{1 31 61 71} May reinstitute after the acute episode is resolved based on clinician judgment.^{40 71}

Specific Populations

Pregnancy

Category C.¹ Abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities.^{1 31 48 71}

Most experts recommend use of insulin during pregnancy.^{1 14 56 64 71 109}

Lactation

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

Discontinue nursing or the drug.^{1 14 71}

Pediatric Use

Safety and efficacy of repaglinide in children <18 years of age not established.^{40 71} However, the American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient’s family.¹⁰⁹

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 5 14 1 5 14 101} (See Absorption: Special Populations under Pharmacokinetics.) No increase in frequency and severity of hypoglycemia in geriatric versus younger patients receiving repaglinide.^{1 14 101}

Individualize antidiabetic therapy when implementing strict glycemic control considering advanced age, comorbid conditions, preexisting clinically relevant microvascular and macrovascular complications or other vascular risk factors, degree of hyperglycemia, and life expectancy.^{31 58}

Hepatic Impairment

Use with caution.^{1 5 59 71}

Renal Impairment

Use with caution.^{1 5 61}

Common Adverse Effects

Hypoglycemia,^{1 5 14 80 81 99 100 101 102 104 105} upper respiratory tract infection,¹ headache,^{1 64 71 80 81} arthralgia,¹ sinusitis,¹ nausea,¹ diarrhea,¹ back pain.¹

Interactions for Repaglinide

Metabolized by CYP3A4 to inactive metabolites.¹

Drugs or Foods Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: potential pharmacokinetic interaction (increased repaglinide AUC and peak blood concentrations).¹

Inducers of CYP3A4: potential pharmacokinetic interaction (decreased repaglinide AUC and peak blood concentrations).^{1 14 59 62 64 71}

Close monitoring of blood glucose concentrations suggested in patients receiving concomitant CYP3A4 inhibitors or inducers.^{40 59 71}

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 5 14 61 64 71 104} Conversely, repaglinide could displace other protein-bound drugs from binding sites.^{1 14 71}

Observe patient for evidence of hypoglycemia or loss of glycemic control when other protein-bound drugs are initiated or withdrawn, respectively, in patients receiving repaglinide.^{1 5 14 71}

Specific Drugs and Foods

Drug or Food	Interaction	Comments
β-Adrenergic blocking agents	Potential for displacement of repaglinide and/or β-adrenergic blocking agents from plasma proteins1 14 71	Observe for evidence of hypoglycemia or loss of glycemic control when β-adrenergic blocker is added to therapy or withdrawn1 5 14 71
Antiretroviral agents, HIV protease inhibitors	Potential inhibition of repaglinide metabolism
Barbiturates	Potential for increased repaglinide metabolism1 14 59 62 64 71	Close monitoring of blood glucose concentrations suggested in patients receiving such concomitant therapy40 59 71
Calcium-channel blocking agents	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe for evidence of altered glycemic control when a calcium-channel blocker is added to therapy or discontinued1 5 14 71
Carbamezapine	Potential for increased metabolism of repaglinide1	Close monitoring of blood glucose concentrations suggested in patients receiving such concomitant therapy40 59 71
Chloramphenicol	Potential for displacement of repaglinide and/or chloramphenicol from plasma proteins1 14 71	Observe for evidence of hypoglycemia or loss of glycemic control when chloramphenicol is added to therapy or discontinued1 5 14 71
Cimetidine	No appreciable effect on repaglinide pharmacokinetics1 14 49 64 71 106
Clarithromycin	Increased AUC and peak plasma concentration of repaglinide1	May necessitate an adjustment in repaglinide dosage1
Clofibrate	May enhance the hypoglycemic effect of repaglinide71 117	Observe for evidence of altered glycemic control when clofibrate is added to therapy or discontinued 1 5 14 71
Corticosteroids	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when corticosteroid is added to therapy or discontinued1 5 14 71
Cyclosporine	Potential inhibition of metabolism of repaglinide14 59 62 64 71
Digoxin	No clinically relevant effect on digoxin pharmacokinetics1 71	Close observation for hypoglycemia or loss or glycemic control suggested when digoxin is added to therapy or discontinued71
Diuretics (e.g., thiazides)	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when thiazides or other diuretics are added to therapy or discontinued1 5 14 71
Erythromycin	Potential inhibition of repaglinide metabolism1 14 59 62 64 71
Estrogens	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when estrogens are added to therapy or discontinued1 5 14 71
Furosemide	In vitro evidence that furosemide decreases the protein binding of repaglinide and increases free circulating repaglinide concentrations64	Interaction not thought to be clinically important64
Gemfibrozil	Increased AUC and plasma repaglinide concentrations and prolonged half-life; may enhance and prolong the hypoglycemic effects of repaglinide1	Should not initiate gemfibrozil therapy in patients taking repaglinide, and those taking gemfibrozil should not begin therapy with repaglinide1
Grapefruit juice	Potential inhibition of repaglinide metabolism71
HMG-CoA reductase inhibitors (statins)	Potential for displacement of repaglinide and/or certain statins from plasma proteins1 14 71	Observe closely for evidence of hypoglycemia or loss of glycemic control when certain statins added to therapy or discontinued1 5 14 71
Isoniazid	May cause hyperglycemia and may exacerbate glycemic control in patients with diabetes mellitus 1 14 61 71	Observe closely for evidence of altered glycemic control when isoniazid is added to therapy or discontinued1 5 14 71
Itraconazole	Potential increase in repaglinide AUC1 With concomitant use of gemfibrozil and itraconazole, increased AUC and prolonged half-life of repaglinide1	Patients already receiving concomitant therapy with repaglinide and gemfibrozil should not receive itraconazole1
Ketoconazole	Increased AUC and peak blood concentrations of repaglinide1
MAO inhibitors	Potential for displacement of repaglinide and/or MAO inhibitors from plasma proteins1 14 71	Observe closely for evidence of hypoglycemia or loss of glycemic control when MAO inhibitors are added to therapy or discontinued1 5 14 71
Niacin	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when niacin is added to therapy or discontinued1 5 14 71
Nifedipine	No clinically relevant effect on nifedipine pharmacokinetics1 71	Close observation for hypoglycemia or loss or glycemic control suggested when nifedipine is added to therapy or discontinued71
NSAIAs	Potential for displacement of repaglinide and/or salicylates from plasma proteins1 14 71	When initiated or withdrawn in patients receiving repaglinide, observe for evidence of hypoglycemia or loss of glycemic control1 5 14 71
Oral contraceptives	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71 Increased peak concentrations of repaglinide and the oral contraceptive components with concomitant use of repaglinide and the fixed combination of levonorgestrel and ethinyl estradiol1 Increased AUC for the ethinyl estradiol component1	Observe closely for evidence of altered glycemic control when oral contraceptives are added to therapy or discontinued1 5 14 71
Phenothiazines	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus 1 14 61 71	Observe closely for evidence of altered glycemic control when phenothiazines are added to therapy or discontinued1 5 14 71
Phenytoin	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when phenytoin added to therapy or discontinued1 5 14 71
Probenecid	Potential for displacement of repaglinide and/or probenecid from plasma proteins1 14 71	Observe closely for evidence of hypoglycemia or loss of glycemic control when probenecid added to therapy or discontinued1 5 14 71
Rifampin	Decrease in rifampin AUC and peak blood concentration1	Close monitoring of blood glucose concentrations suggested in patients receiving such concomitant therapy40 59 71
Sulfonamides	Potential for displacement of repaglinide and/or sulfonamides from plasma proteins1 14 71	Observe closely for evidence of hypoglycemia or loss of glycemic control when sulfonamides are added to therapy or discontinued1 5 14 71
Sympathomimetics	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when sympathomimetics are added to therapy or discontinued1 5 14 71
Theophylline	No clinically relevant effect on theophylline pharmacokinetics1 71	Close observation for hypoglycemia or loss of glycemic control suggested when theophylline is added to therapy or discontinued71
Thyroid preparations	May cause hyperglycemia and exacerbate glycemic control in patients with diabetes mellitus1 14 61 71	Observe closely for evidence of altered glycemic control when thyroid preparations are added to therapy or discontinued1 5 14 71
Tolbutamide	In vitro evidence that tolbutamide decreases the protein binding of repaglinide64	Interaction not thought to be clinically important64
Warfarin	In vitro evidence that warfarin decreases the protein binding of repaglinide; not thought to be clinically relevant64	Close observation for hypoglycemia or loss of glycemic control suggested when warfarin is added to therapy or discontinued1 5 14 71

Repaglinide Pharmacokinetics

Absorption

Bioavailability

Approximately 56% (absolute).^{1 5 14 61 71}

Peak plasma drug concentrations attained within approximately 1 hour.^{1 10 14 56 59 60 61 62 64 65 68 71 100 107}

Onset

Peak serum insulin concentrations achieved in approximately 1.5 hours.¹¹³ Maximum glycemic effect within 3–3.5 hours.^{2 61 79} Most of the hypoglycemic effect occurs within 1–3 weeks.^{1 5 11 14 61 65 71 80 113}

Duration

Plasma insulin concentrations remain elevated for 4 hours after each meal in patients with type 2 diabetes mellitus;¹⁰ return toward premeal concentrations between meals and at bedtime.^{1 2 5 11 14 61 64 71}

Food

Food may delay and reduce the extent of GI absorption.^{1 5 14 59 61 71} 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.^{14 59}

Special Populations

Greater systemic exposure (as determined by peak plasma concentrations and AUCs) to repaglinide in patients with hepatic impairment.^{1 5 14 61 71 105}

Increases in plasma concentrations and AUC of repaglinide in patients with severe renal impairment (Cl_cr 20–40 mL/minute).^{1 5 59 60 61 64 71 104} Such alterations not found in patients with mild to moderate renal impairment.^{1 5 71 104}

No pharmacokinetic differences (peak plasma concentration, AUC) observed in geriatric individuals (≥65 years of age) compared with healthy younger individuals.^{1 5 14 101}

Distribution

Extent

Distributes into erythrocytes.¹⁰⁷

Distributes into milk in rats; not known whether distributed into human milk.^{1 14}

Plasma Protein Binding

>98%.^{1 5 14 61 64 71 104}

Elimination

Metabolism

Rapidly metabolized by CYP3A4 to inactive metabolites.^{1 5 14 59 62 64 65 67 71 80 81 99 100 101 104 105 107}

Elimination Route

Extensively metabolized in liver and excreted into bile and feces (90%) as metabolites.^{1 3 5 14 40 56 59 60 61 64 68 71 73 80 99 104 106 107}

Small amount excreted in urine (8%) principally as metabolites.^{1 5 14 56 59 60 61 64 65 68}