Repaglinide

Indications
Repaglinide is indicated as an adjunct to diet and exercise to lower the blood glucose level in patients with type 2 diabetes mellitus (NIDDM) whose hyperglycaemia cannot be controlled satisfactorily by diet and exercise alone. It is also indicated for use in combination with Metformin to lower blood glucose in patients whose hyperglycaemia cannot be controlled by exercise, diet, and either Repaglinide or Metformin alone. Repaglinide binds to specific receptors in the cell membrane leading to the closure of ATP dependent K+ channels and the depolarisation of cell membrane. This in turn, leads to Ca++ influx, increased intracellular Ca++ and the stimulation of insulin secretion.

Therapeutic Class
Meglitinide Analogues

Pharmacology
Repaglinide stimulates release of insulin from pancreatic β-cells by inhibiting K efflux via closure of ATP regulated K channels. This results in depolarization of the cell and opening of voltage-dependent Ca channels, which increases influx of Ca into the beta cells and causes release of insulin.

Dosage & Administration
Repaglinide has to be taken just before or up to 30 minutes before the meal. Repaglinide can be taken two, three or four times a day, depending on how many meals are taken. If a meal is missed, Repaglinide should also be avoided. If an extra meal is taken, an extra dose of Repaglinide should be taken with that meal. If a dose of Repaglinide is missed, it should not be taken between meals.
Rather the usual dose should be taken before the next meal. The dose ranges from 0.5 to 4 mg before each meal. The starting dose of Repaglinide in patients with HbA1c <8% is 0.5 mg before each meal. In patients with HbA1c >8% the starting dose is 1 or 2 mg before each meal. The dose may be increased gradually up to 4 mg before each meal.

Interaction
The dose of Repaglinide may need to be adjusted, if taken with other medications. The possible interactions of Repaglinide with other drugs are:
i) Inhibitors of the cytochrome P450 enzyme system (azole antifungals and macrolides) may lead to lower Repaglinide clearance and longer half life.
ii) Inducers of the cytochrome P450 enzyme system (Rifampin, Phenobarbital, Carbamazepine, Troglitazone, etc.) may accelerate Repaglinide metabolism and shorten its effect.
iii) Cimetidine has no significant effect on Repaglinide absorption or clearance.
iv) Repaglinide has no significant effect on Digoxin, Theophyllin, or Warfarin.
v) Highly protein bound drugs (e.g., NSAIDs) may increase the plasma level of unbound Repaglinide and potentiate its glucose lowering effect. Thus, co-administration of these drugs with Repaglinide may increase the risk of hypoglycaemia.
vi) The risk of hypoglycaemia may also be increased when hypoglycaemic agents are co-administered with certain drugs such as salicylates, sulphonamides, Chloramphenicol, coumarins, Probenecid, monoamine oxidase (MAO) inhibitors, and adrenergic blockers.

Contraindications
Repaglinide is contraindicated in patients with diabetic ketoacidosis, with or without coma, in patients with type I diabetes and in patients with known hypersensitivity to any of the components of the product.

Side Effects
Hypoglycaemia is possible with all blood glucose lowering drugs. If there are symptoms of low blood glucose (for example, headache, dizziness, tiredness, nervousness or shakiness, rapid heartbeat, or nausea), blood glucose should be tested right away. If it is low (less than 70 mg/dl on a home glucose meter), a simple carbohydrate food (for example, orange juice, quick dissolving sugar, candies, or glucose tablets) should be taken. If the symptoms do not go away, doctor should be informed. Some of the other common symptoms reported by patients taking Repaglinide include cold and flu-like symptoms, diarrhoea, joint ache, and back pain. There is some evidence that oral anti-diabetic drugs may increase the risk of heart problems. But experts are not sure what the real risk is, if any, from taking oral anti-diabetic drugs.

Pregnancy & Lactation
In pregnancy, safety of Repaglinide has not been established. Hence, Repaglinide should be used during pregnancy only if it is clearly needed. It is not known whether Repaglinide is excreted in human milk. Because many drugs are excreted in human milk and because of potential for serious adverse reactions in nursing infants from Repaglinide, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Precautions & Warnings
Repaglinide should also be used with caution in renal and hepatic insufficiency.

Overdose Effects
Patients receiving up to 80 mg of Repaglinide developed few adverse effects other than lowering of blood glucose. Hypoglycemia did not occur when meals were given with these high doses. Severe hypoglycemic reactions with coma, seizure or other neurological impairment occur infrequently.

Storage Conditions
Store below 25° C. Protect from moisture.