Repaglinide

Pronunciation: (rehPAGlihnide)
Class: Antidiabetic agent

Trade Names

Prandin
- Tablets 0.5 mg
- Tablets 1 mg
- Tablets 2 mg

GlucoNorm (Canada)

Pharmacology

Decreases blood glucose by stimulating insulin release from the pancreas.

Pharmacokinetics

Absorption

Rapidly and completely absorbed from GI tract. T _max is 1 h (single and multiple doses). Absolute bioavailability is 56%. Mean C _max is decreased 20%; AUC is decreased 12.4% by food.

Distribution

Vd is 31 L (IV). Protein binding and binding to human albumin is greater than 98%.

Metabolism

Completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid. CYP-450 enzymes, mainly CYP3A4, are involved in Ndealkylation to oxidized dicarboxylic acid (M2), then to the aromatic amine (M1), and acyl glucuronide (M7) (inactive metabolites).

Elimination

Eliminated in feces (90% recovered) and urine (8%). Total body Cl is 38 L/h (IV). The t _½ is about 1 h.

Special Populations

Renal Function Impairment

AUC and C _max increased in severe renal function impairment.

Hepatic Function Impairment

Higher and more prolonged serum concentrations in patients with moderate to severe hepatic function impairment.

Indications and Usage

Adjunct to diet and exercise to lower blood glucose in patients with noninsulindependent diabetes mellitus (type 2) whose hyperglycemia cannot be controlled by diet and exercise alone. Can be used with metformin or thiazolidinediones (eg, rosiglitazone) when hyperglycemia cannot be controlled by exercise, diet, and monotherapy with metformin, sulfonylureas, repaglinide, or thiazolidinediones.

Contraindications

Insulindependent (type 1) diabetes; diabetic ketoacidosis with or without coma; hypersensitivity to repaglinide or its ingredients.

Dosage and Administration

No fixed dosage regimen; periodically monitor blood glucose to determine minimum effective dose. Double preprandial dose up to 4 mg with each meal until satisfactory response is achieved (max dose, 16 mg/day). Allow 1 wk to elapse after each dose adjustment to assess response.

Patients Not Previously Treated or Whose HbA _1c is Less Than 8%
Adults

PO Initial dose is 0.5 mg with each meal.

Patients Previously Treated or Whose HbA _1c is More Than or Equal to 8%
Adults

PO Initial dose 1 to 2 mg with each meal.

Combination therapy
Adults

PO The starting dose and dosage adjustments for combination therapy are the same as repaglinide monotherapy.

General Advice

• Administer with meals to reduce risk of hypoglycemia.
• Administer immediately before each meal or as long as 30 min before the meal.

Storage/Stability

Store tablets at controlled room temperature (below 77°F). Keep tightly closed and protect from moisture.

Drug Interactions

Drugs that induce CYP3A4 (eg, barbiturates, carbamazepine, rifampin, troglitazone)

May increase repaglinide metabolism.

Drugs that inhibit CYP3A4 (eg, erythromycin, ketoconazole, miconazole)

May inhibit repaglinide metabolism.

Drug that produce hyperglycemia (eg, calcium channel blockers, corticosteroids, diuretics, estrogens and oral contraceptives, isoniazid, nicotinic acid, phenothiazines, phenytoin, sympathomimetics, thyroid products)

May lead to loss of glycemic control. Monitor patient and adjust therapy when these agents are started or stopped.

Gemfibrozil

May result in enhanced and prolonged blood glucoselowering effects of repaglinide. Patients receiving repaglinide should not start gemfibrozil; patients receiving gemfibrozil should not start taking repaglinide.

Gemfibrozil plus itraconazole

Itraconazole and gemfibrozil have a synergistic inhibitory effect on repaglinide metabolism. Patients taking gemfibrozil and repaglinide should not receive itraconazole.

Levonorgestrel and ethinyl estradiol

Plasma levels of these agents and those of repaglinide may be elevated.

Protein bound drugs (eg, betaadrenergic blocking agents, MAOIs, NSAIDs, probenecid, salicylates, sulfonamides)

May potentiate hypoglycemic effect of repaglinide.

Simvastatin

Repaglinide plasma levels may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Serious CV reactions (4%); cardiac ischemic reactions (2%); deaths caused by CV reactions (0.5%).

CNS

Headache (11%).

Dermatologic

Alopecia, StevensJohnson syndrome (postmarketing).

EENT

Rhinitis (7%).

GI

Diarrhea, nausea (5%); dyspepsia (4%); constipation, vomiting (3%); tooth disorder (2%); pancreatitis (postmarketing).

Genitourinary

UTI (3%).

Hematologic-Lymphatic

Thrombocytopenia, leukopenia (less than 1%); hemolytic anemia, severe hepatic dysfunction (postmarketing).

Metabolic-Nutritional

Hypoglycemia (31%).

Musculoskeletal

Arthralgia, back pain (6%).

Respiratory

Upper respiratory tract infection (16%); sinusitis, bronchitis (6%).

Miscellaneous

Chest pain, paresthesia (3%); allergy (2%).

Precautions

Monitor Monitor blood glucose to determine minimum effective dose, detect primary failure, and to detect secondary failure. Monitor glycosylated hemoglobin levels (A 1c ) to determine patient's longerterm response to therapy.

Pregnancy

Category C . Insulin is recommended to be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Elderly may be more susceptible to the hypoglycemic action of repaglinide. Hypoglycemia may be difficult to recognize in the elderly.

Renal Function

Initiate therapy with 0.5 mg dose in patients with severe renal function impairment and use caution when titrating dose.

Hepatic Function

Use with caution. Allow longer intervals between dosage adjustments.

Hypoglycemia

Proper patient selection, dosage, and instructions to patients are important to avoid hypoglycemic episodes. Elderly, debilitated, or malnourished patients, and patients with adrenal, pituitary, hepatic, or severe renal function impairment may be particularly susceptible to the hypoglycemic action of glucoselowering drugs.

Loss of glycemic control

Patients stabilized on any diabetic regimen may experience loss of glycemic control when exposed to stress, including trauma, fever, infection, or surgery. At such times, it may be necessary to discontinue repaglinide and administer insulin.

Overdosage

Symptoms

Coma, hypoglycemia, impairment, neurologic, seizure.

Patient Information

• Advise patient or caregiver to read the patient information leaflet before using the first time and with each refill.
• Instruct patient to take prescribed dose immediately before or up to 30 min before each meal. Advise patient to add a dose before an extra meal.
• Instruct patient that if meal is missed, to skip the dose for that meal to reduce risk of hypoglycemia.
• Educate patient or caregiver regarding diabetes and its management, including target ranges for blood sugar control. Instruct patient or caregiver that this medication is not a substitute for diet and exercise, and to continue to follow prescribed regimens.
• Educate patient or caregiver regarding potential longterm complications of diabetes and the need for regular general physical and eye examinations.
• Ensure patient or caregiver understands how to use home glucose monitor and has a plan for monitoring and recording blood sugar measurements (eg, log). Advise patient to take log to each visit with health care provider.
• Educate patient regarding value of periodic A _1c testing to confirm level of glucose control.
• Review symptoms of hypoglycemia (eg, low blood sugar) and hyperglycemia (eg, high blood sugar) and action plans to undertake in the event either occur.
• Advise patient to discuss with health care provider a plan for managing each of the following situations: medication dosing during intercurrent conditions (eg, infection, sick days, stress, trauma, vomiting); accidental ingestion of too little or too much medication; missed dose of medication; inadequate food intake or a skipped meal; travel across time zones; change in physical activity.
• Instruct patient to notify health care provider if experiencing severe, continuous, or frequent hypoglycemic episodes; hypoglycemic episodes with few or no warning symptoms; or continuous or severe hyperglycemia.
• Advise patient to carry medical identification (eg, card, bracelet) of diabetes.

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