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Uses

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.

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.

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.

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.

Dosage and Administration

General

• Carefully individualize dosage based on patient response and tolerance.
• 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.
• (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.)
• Monitor patients with regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess therapeutic response and minimum effective dosage. American Diabetes Association (ADA) and some clinicians currently suggest that routine blood glucose monitoring should include fasting and 2-hour postprandial blood glucose concentrations.
• 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. 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.
• 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. 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.
• 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. If secondary failure occurs with combined metformin and repaglinide therapy, most clinicians currently recommend discontinuance of oral antidiabetic agents and initiation of insulin therapy. However, other options include the addition of a third oral antidiabetic agent (e.g., acarbose, a thiazolidinedione) before switching to insulin therapy. (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.
• 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.

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, may add metformin or a thiazolidinedione. 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.
• Titrate initial dosage of repaglinide during combination therapy as with repaglinide monotherapy. 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. Failure to titrate the dosage of each drug to the minimum effective level could result in an increased risk of hypoglycemic episodes.
• 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. Other options include adding a third oral antidiabetic agent (e.g., acarbose, a thiazolidinedione) before switching to insulin therapy. (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. Administration with food may affect the extent of absorption. (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.

If a meal is skipped or added, skip or add a dose, respectively, for that meal.

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%).

Patients with glycosylated hemoglobin ≥8% despite treatment with other oral antidiabetic agents: initially, 1 or 2 mg with or preceding each meal.

Approximately 90% of maximal glucose-lowering effect is achieved with dosage of 1 mg 3 times daily.

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.

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

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; higher dosages have been used. (See Diabetes Mellitus under Dosage and Administration.)

Special Populations

Dosage in Renal Impairment

Mild to moderate renal dysfunction: No adjustment in initial dosage necessary. May administer usual initial dosage but use caution with subsequent dosage increases.

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

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

Dosage in Hepatic Impairment

Use with caution. 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. Some clinicians suggest lower initial dosage in patients with hepatic impairment.