Repaglinide

Pronunciation

(re pa GLI nide)

U.S. Brand Names

Prandin®

Generic Available

Canadian Brand Names

GlucoNorm®; Prandin®

Use

Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM); may be used in combination with metformin or thiazolidinediones

Pregnancy Risk Factor

Pregnancy Implications

Safety in pregnant women has not been established. Use during pregnancy only if clearly needed. Abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to repaglinide or any component of the formulation; diabetic ketoacidosis, with or without coma (treat with insulin); type 1 diabetes (insulin dependent, IDDM)

Warnings/Precautions

Use with caution in patients with hepatic or renal 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). Safety and efficacy have not been established in pediatric patients.

Adverse Reactions

>10%:

Central nervous system: Headache (9% to 11%)

Endocrine & metabolic: Hypoglycemia (16% to 31%)

Respiratory: Upper respiratory tract infection (10% to 16%)

1% to 10%:

Cardiovascular: Chest pain (2% to 3%)

Gastrointestinal: Nausea (3% to 5%), heartburn (2% to 4%), vomiting (2% to 3%) constipation (2% to 3%), diarrhea (4% to 5%), tooth disorder (<1% to 2%)

Genitourinary: Urinary tract infection (2% to 3%)

Neuromuscular & skeletal: Arthralgia (3% to 6%), back pain (5% to 6%), paresthesia (2% to 3%)

Respiratory: Sinusitis (3% to 6%), rhinitis (3% to 7%), bronchitis (2% to 6%)

Miscellaneous: Allergy (1% to 2%)

<1%: Anaphylactoid reaction, leukopenia, liver function tests increased, thrombocytopenia

Postmarketing and/or case reports: Alopecia, hemolytic anemia, hepatic dysfunction (severe), pancreatitis, Stevens-Johnson syndrome

Overdosage/Toxicology

Symptoms of severe hypoglycemia include seizures, cerebral damage, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma. Management includes glucose administration (oral for milder hypoglycemia or by injection in more severe forms) and symptomatic treatment.

Drug Interactions

Substrate of CYP2C8/9 (major), 3A4 (major)

CYP2C8/9 inducers: CYP2C8/9 inducers may decrease the levels/effects of repaglinide. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: CYP2C8/9 inhibitors may increase the levels/effects of repaglinide. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of repaglinide. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of repaglinide. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Gemfibrozil: Gemfibrozil may increase the serum concentration of repaglinide (prolonged, severe hypoglycemia has been reported). The addition of itraconazole may augment the effects of gemfibrozil on repaglinide. Consider alternative therapy.

HMG-CoA reductase inhibitors (eg, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin): May increase repaglinide concentrations by decreasing metabolism.

Macrolide antibiotics (limited to agents which inhibit CYP3A4 - clarithromycin, erythromycin, troleandomycin): May increase repaglinide concentrations by decreasing metabolism. Clarithromycin increases repaglinide AUC by 40%; monitor.

Oral contraceptives: Repaglinide may increase serum concentrations of contraceptives.

Estrogens (eg, estradiol, ethinyl estradiol, mestranol): May increase repaglinide concentrations.

Progestins: May increase repaglinide concentrations.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may cause hypoglycemia).

Food: When given with food, the AUC of repaglinide is decreased.

Herb/Nutraceutical: St John's wort may decrease repaglinide levels. Avoid gymnema, garlic (may cause hypoglycemia).

Stability

Do not store above 25°C (77°F). Protect from moisture.

Mechanism of Action

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

Pharmacodynamics/Kinetics

Onset of action: Single dose: Increased insulin levels: ~15-60 minutes

Duration: 4-6 hours

Absorption: Rapid and complete

Distribution: Vd: 31 L

Protein binding, plasma: >98%

Metabolism: Hepatic via CYP3A4 isoenzyme and glucuronidation to inactive metabolites

Bioavailability: Mean absolute: ~56%

Half-life elimination: 1 hour

Time to peak, plasma: ~1 hour

Excretion: Within 96 hours: Feces (~90%, <2% as parent drug); Urine (~8%)

Dosage

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

Initial: For patients not previously treated or whose Hb A1c is <8%, the starting dose is 0.5 mg. For patients previously treated with blood glucose-lowering agents whose Hb A1c is 8%, the initial dose is 1 or 2 mg before each 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 1 week.

Combination therapy: If repaglinide monotherapy does not result in adequate glycemic control, metformin or a thiazolidinedione may be added. Or, if metformin or thiazolidinedione 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 A1c 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.

Dosing adjustment in renal impairment:

Clcr 40-80 mL/minute (mild to moderate renal dysfunction): Initial dosage adjustment does not appear to be necessary.

Clcr 20-40 mL/minute: Initiate 0.5 mg with meals; titrate carefully.

Dosing adjustment in hepatic impairment: Use conservative initial and maintenance doses. Use longer intervals between dosage adjustments.

Administration

Administer repaglinide 15-30 minutes before meals. Patients who are anorexic or NPO, may need to have their dose held to avoid hypoglycemia.

Monitoring Parameters

Periodically monitor fasting blood glucose and glycosylated hemoglobin (Hb A1c) levels with a goal of decreasing these levels towards the normal range. During dose adjustment, fasting glucose can be used to determine response.

Reference Range

Target range: Adults:

Fasting blood glucose: <120 mg/dL

Glycosylated hemoglobin: <7%

Dietary Considerations

Administer repaglinide 15-30 minutes before meals. Dietary modification based on ADA recommendations is a part of therapy. May cause hypoglycemia. Must be able to recognize symptoms of hypoglycemia (palpitations, tachycardia, sweaty palms, diaphoresis, lightheadedness).

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. 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 consulting prescriber. Follow dietary and lifestyle directions of prescriber or diabetic educator. Avoid alcohol. You will be instructed in signs of hypo- or hyperglycemia by prescriber or diabetic educator; be alert for adverse hypoglycemia (lightheadedness, tachycardia or palpitations, sweaty palms or profuse perspiration, yawning, tingling of lips and tongue, seizures, or change in sensorium) and follow prescriber's instructions for intervention. May cause headache or mild GI effects during first weeks of therapy (nausea, vomiting, diarrhea, constipation, heartburn), if these do not diminish, consult prescriber for approved medication. Report chest pain; respiratory difficulty or symptoms of upper respiratory infection; urinary tract infection (burning or itching on urination); muscle pain or back pain; or other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

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

Dosage Forms

Tablet: 0.5 mg, 1 mg, 2 mg

References

Niemi M, Backman JT, Neuvonen M, et al, "Effects of Gemfibrozil, Itraconazole, and Their Combination on the Pharmacokinetics and Pharmacodynamics of Repaglinide: Potentially Hazardous Interaction Between Gemfibrozil and Repaglinide," Diabetologia , 2003, 46(3):347-51.

International Brand Names

GlucoNorm® (CA); Novonorm® (AR, AT, AU, BE, CH, CO, CY, DE, DK, EG, ES, FI, FR, GB, HR, HU, IE, IL, IT, JO, KW, LB, NL, NO, NZ, PL); Novo Norm® (RO); Novonorm® (RU, SE, SG, SI, SY, TH, TR, YU); Prandin® (BR, CA, ES); Rapilin® (IN); Sestrine® (AR)

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