No

Antidiabetic Agent (Miscellaneous)

Management of noninsulin-dependent diabetes mellitus (type 2)

In combination with metformin to lower blood glucose in patients whose hyperglycemia cannot be controlled by exercise, diet and either agent alone

C

Clinical effects on the fetus: Safety in pregnant women has not been established. Use during pregnancy only if clearly needed. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy. It is not known whether repaglinide is excreted in breast milk. Because the potential for hypoglycemia in nursing infants may exist, decide whether to discontinue repaglinide or discontinue breast-feeding. If repaglinide is discontinued and if diet alone is inadequate for controlling blood glucose, consider insulin therapy.

Diabetic ketoacidosis, with or without coma (treat with insulin); type 1 diabetes; hypersensitivity to the drug or its inactive ingredients

Use with caution in patients with hepatic impairment. All oral hypoglycemic agents are capable of producing hypoglycemia. Proper patient selection, dosage, and instructions to the patients are important to avoid hypoglycemic episodes. It may be necessary to discontinue repaglinide and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

At higher dosages, sulfonylureas may block the ATP-sensitive potassium channels, which may correspond to an increased risk of cardiovascular events. In May, 2000, the National Diabetes Center issued a warning to avoid the use of sulfonylureas at higher dosages (repaglinide daily doses >1.5 mg).

>10%:

Central nervous system: Headache

Endocrine & metabolic: Hyperglycemia, hypoglycemia, related symptoms

1% to 10%:

Cardiovascular: Chest pain

Gastrointestinal: Nausea, epigastric fullness, heartburn, constipation, diarrhea, anorexia, tooth disorder

Genitourinary: Urinary tract infection

Neuromuscular: Arthralgia, back pain, paresthesia

Miscellaneous: Allergy

Symptoms of overdose include severe hypoglycemia, seizures, cerebral damage, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma

Intoxications are best managed with glucose administration (oral for milder hypoglycemia or by injection in more severe forms) and symptomatic management

CYP3A4 enzyme substrate

Increased effect: Agents that inhibit cytochrome P-450 3A4 (ketoconazole, miconazole) and antibacterial agents (erythromycin) may increase repaglinide concentrations

Increased toxicity: Since this agent is highly protein bound, the toxic potential is increased when given concomitantly with other highly protein bound drugs (ie, phenylbutazone, oral anticoagulants, hydantoins, salicylates, NSAIDs, sulfonamides) - increase hypoglycemic effect

Nonsulfonylurea hypoglycemic agent of the meglitinide class (the nonsulfonylurea moiety of glyburide) used in the management of type 2 diabetes mellitus; stimulates insulin release from the pancreatic beta cells

Onset of action: Oral: Insulin levels in the serum begin to increase within 15-60 minutes after a single dose

Duration: Up to 24 hours

Absorption: Rapidly and completely from the GI tract with peak plasma drug levels within 1 hour

Distribution: V_d: 31 L

Protein binding, plasma: >98%

Metabolism: Completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid. The cytochrome P-450 enzyme system (specifically 3A4) is involved in metabolism (inactive metabolites)

Bioavailability, mean absolute: ~56%

Elimination: ~90% in the feces and ~8% within 96 hours

Adults: Oral: Should be taken within 15 minutes of the meal, but time may vary from immediately preceding the meal to as long as 30 minutes before the meal

Dose adjustment: Determine dosing adjustments by blood glucose response, usually fasting blood glucose. Double the preprandial dose up to 4 mg until satisfactory blood glucose response is achieved. At least 1 week should elapse to assess response after each dose adjustment.

Dose range: 0.5-4 mg taken with meals. Repaglinide may be dosed preprandial 2, 3 or 4 times/day in response to changes in the patient's meal pattern. Maximum recommended daily dose: 16 mg.

Patients receiving other oral hypoglycemic agents: When repaglinide is used to replace therapy with other oral hypoglycemic agents, it may be started the day after the final dose is given. Observe patients carefully for hypoglycemia because of potential overlapping of drug effects. When transferred from longer half-life sulfonylureas (eg, chlorpropamide), close monitoring may be indicated for up to greater than or equal to 1 week.

Combination therapy: If repaglinide monotherapy does not result in adequate glycemic control, metformin may be added. Or, if metformin therapy does not provide adequate control, repaglinide may be added. The starting dose and dose adjustments for combination therapy are the same as repaglinide monotherapy. Carefully adjust the dose of each drug to determine the minimal dose required to achieve the desired pharmacologic effect. Failure to do so could result in an increase in the incidence of hypoglycemic episodes. Use appropriate monitoring of FPG and Hb A_1c measurements to ensure that the patient is not subjected to excessive drug exposure or increased probability of secondary drug failure. If glucose is not achieved after a suitable trial of combination therapy, consider discontinuing these drugs and using insulin.

At higher dosages, sulfonylureas may block the ATP-sensitive potassium channels, which may correspond to an increased risk of cardiovascular events. In May, 2000, the National Diabetes Center issued a warning to avoid the use of sulfonylureas at higher dosages (repaglinide daily doses >1.5 mg); see Warnings/Precautions.

Dosing adjustment/comments in renal impairment: Initial dosage adjustment does not appear to be necessary, but make subsequent increases carefully in patients with renal function impairment or renal failure requiring hemodialysis

Dosing adjustment in hepatic impairment: Use conservative initial and maintenance doses and avoid use in severe disease

Food: When given with food, the AUC of repaglinide is decreased; administer repaglinide before meals

Glucose: Decreases blood glucose concentration. Hypoglycemia may occur. Educate patients how to detect and treat hypoglycemia. Monitor for signs and symptoms of hypoglycemia. Administer glucose if necessary. Evaluate patient's diet and exercise regimen. May need to decrease or discontinue dose of sulfonylurea.

Periodically monitor fasting blood glucose and glycosylated hemoglobin (Hb A_1c) levels with a goal of decreasing these levels towards the normal range. During dose adjustment, fasting glucose can be used to determine response.

Target range: Adults:

Glycosylated hemoglobin: <7%

None reported

Repaglinide is a CYP3A4 substrate; monitor glucose when used with an enzyme inducer (carbamazepine, barbiturates) or an inhibitor (nefazodone, fluvoxamine)

No information available to require special precautions

No effects or complications reported

Take this medication exactly as directed - 3-4 times a day, 15-30 minutes prior to a meal. If you skip a meal (or add an extra meal) skip (or add) a dose for that meal. Do not change dosage or discontinue without first consulting prescriber. It is important to follow dietary and lifestyle recommendations of prescriber. You will be instructed in signs of hypo-/hyperglycemia by prescriber or diabetic educator; be alert for adverse hypoglycemia (tachycardia, profuse perspiration, tingling of lips and tongue, seizures, or change in sensorium) and follow prescriber's instructions for intervention. You may experience mild side effects during first weeks of therapy (eg, headache, diarrhea, constipation, bloating); if these do not diminish, notify prescriber. Increasing dietary fiber or fluids and increasing exercise may reduce constipation (for persistent diarrhea consult prescriber). Mild analgesics may reduce headaches. Frequent mouth care, small frequent meals, chewing gum, sucking lozenges may help reduce nausea, vomiting, or heartburn. Report chest pain, palpitations, or irregular heartbeat; respiratory difficulty or symptoms of upper respiratory infection; urinary tract infection (burning or itching on urination); muscle pain or back pain; or persistent GI problems. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Patients who are anorexic or NPO, may need to have their dose held to avoid hypoglycemia

Tablet : 0.5 mg, 1 mg, 2 mg