repaglinide
Prandin

Available forms
Available by prescription only
Tablets: 0.5 mg, 1 mg, 2 mg

Indications and dosages
 Adjunct to diet and exercise in lowering blood glucose levels in patients with type 2 diabetes mellitus whose hyperglycemia can’t be controlled by diet and exercise alone; adjunct to diet, exercise and metformin. Adults: For patients not previously treated or whose glycosylated hemoglobin (HbA_1c) is below 8%, starting dose is 0.5 mg P.O. given 15 minutes before each meal; however, time may vary from immediately before to as long as 30 minutes before meal. For patients previously treated with glucose-lowering drugs and whose HbA_1c is 8% or more, initial dose is 1 to 2 mg P.O. with each meal. Recommended dosage range is 0.5 to 4 mg with meals b.i.d., t.i.d., or q.i.d. Maximum, 16 mg daily.
 Dosage should be determined by blood glucose response. May double dosage up to 4 mg with each meal until satisfactory blood glucose response is achieved. At least 1 week should elapse between dosage adjustments to assess response to each dose.
 Metformin may be added if repaglinide monotherapy is inadequate; no repaglinide dosage adjustment is needed.

Pharmacodynamics
Antidiabetic action: Stimulates the release of insulin from beta cells in the pancreas. Repaglinide closes ATP-dependent potassium channels in the beta cell membrane, which causes depolarization of the B-cell and opening of the calcium channels. The increased calcium influx induces insulin secretion; the overall effect is to lower the blood glucose level.

Pharmacokinetics
Absorption: Rapidly and completely absorbed with oral administration.
Distribution: Mean volume of distribution after I.V. administration during clinical trial was 31 L; protein-binding to albumin exceeded 98%.
Metabolism: Completely metabolized by oxidative biotransformation and conjugation with glucuronic acid. The P-450 isoenzyme system (specifically CYP 3A4) has also been shown to be involved in N-dealkylation of repaglinide. All metabolites are inactive and don’t contribute to the blood glucose-lowering effect.
Excretion: About 90% of dose occurs in the feces as metabolites. About 8% of a dose is recovered in the urine as metabolites and less than 0.1% as parent drug. Half-life is about 1 hour.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or its components and in those with insulin-dependent diabetes mellitus or ketoacidosis. Use cautiously in patients with hepatic insufficiency in whom reduced metabolism could cause elevated blood levels of repaglinide and hypoglycemia.

Interactions
Drug-drug. Barbiturates, carbamazepine, rifampin: May increase repaglinide metabolism. Monitor glucose levels.
Beta blockers, chloramphenicol, coumarin, MAO inhibitors, NSAIDs, other highly protein-bound drugs, probenecid, salicylates, sulfonamides: May potentiate hypoglycemic action of repaglinide. Monitor glucose levels.
Calcium channel blockers, corticosteroids, estrogens, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazines, phenytoin, sympathomimetics, thiazides and other diuretics, thyroid products: May produce hyperglycemia. Monitor glucose levels.
Erythromycin, ketoconazole, miconazole, and similar inhibitors of the P-450 cytochrome system 3A4: May inhibit repaglinide metabolism. Monitor glucose levels.
Drug-herb. Aloe, bitter melon, bilberry leaf, burdock, dandelion, fenugreek, garlic, ginseng: May improve blood glucose control, requiring reduced antidiabetic dosage. Explain this effect to patient.

Adverse reactions
CNS: headache.
CV: chest pain, angina.
EENT: rhinitis, sinusitis.
GI: nausea, diarrhea, constipation, vomiting, dyspepsia, tooth disorder.
GU: urinary tract infection.
Metabolic: HYPOGLYCEMIA. 
Musculoskeletal: arthralgia, back pain.
Respiratory: bronchitis, upper respiratory tract infection.

Effects on lab test results
• May increase or decrease glucose levels.

Overdose and treatment
Overdose increases the intended effect of lowering blood glucose levels.
 If patient is conscious and has no loss of neurologic status, treat hypoglycemia aggressively with oral glucose and adjustment to dosage or meal pattern. Monitor patient closely for 24 to 48 hours because hypoglycemia may recur after apparent recovery. If patient has severe hypoglycemia with coma, seizure, or other neurologic impairment, treat immediately with I.V. dextrose 50% solution followed by a continuous infusion of glucose 10% solution. Monitor blood glucose levels carefully.

Special considerations
• Administration of other oral antidiabetics may increase CV mortality compared with diet treatment alone. Although not specifically evaluated for repaglinide, this warning may apply.
• Monitor patient’s blood glucose levels periodically to determine minimum effective dose.
• Monitor long-term efficacy by measuring HbA_1c levels every 3 months.
• Loss of glycemic control can occur during stress, such as fever, trauma, infection, or surgery. If this occurs, stop drug and give insulin.
• Hypoglycemia may be difficult to recognize in elderly patients and those who take beta blockers.
• Increase dosage cautiously in patients with impaired renal function who need dialysis.
Breast-feeding patients
• Although it isn’t known if drug appears in breast milk, studies in animals have indicated excretion similar to other glucose-lowering drugs. Because a breast-fed infant has a risk of hypoglycemia, a decision should be made to discontinue drug or breast-feeding.
Pediatric patients
• No studies have been performed in children to determine safety and efficacy.
Geriatric patients
• Elderly patients show no increase in the frequency or severity of hypoglycemia.

Patient education
• Instruct patient on importance of diet and exercise in combination with drug therapy.
• Discuss symptoms of hypoglycemia with patient and family.
• Tell patient to take drug before meals, usually 15 minutes before start of meal; however, time can vary from immediately preceding meal to up to 30 minutes before meal.
• Tell patient to skip a dose if he skips a meal or add an extra dose if he adds a meal.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use