Repaglinide

(BAN, USAN, rINN)
Repaglinide Chemical formula
Synonyms: AG-EE-6232W; AG-EE-623-ZW; Repaglinid; Repaglinida; Repaglinidas; Répaglinide; Repaglinidi; Repaglinidum. (+)-2-Ethoxy{[(S)2-Ethoxy-4-{[1-(o-piperidinophenyl)-3-methylbutyl]carbamoylmethyl}benzoic acid.
Cyrillic synonym: Репаглинид.

💊 Chemical information

Chemical formula: C27H36N2O4 = 452.6.
CAS — 135062-02-1.
ATC — A10BX02.
ATC Vet — QA10BX02.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Repaglinide). A white or almost white powder. It exhibits polymorphism. Practically insoluble in water; freely soluble in dichloromethane and in methyl alcohol. Protect from light.

USP 31

(Repaglinide). A white to off-white solid. Soluble in methyl alcohol. Store in airtight containers.

💊 Adverse Effects and Precautions

Repaglinide may cause gastrointestinal adverse effects including abdominal pain, diarrhoea, constipation, nausea, and vomiting. Hypoglycaemia (usually mild), back and joint pain, hypersensitivity reactions including pruritus, rashes and urticaria, and elevated liver enzyme values may occur. There have been rare cases of transient visual disturbances attributed to changes in blood glucose concentrations associated with starting repaglinide treatment. There have also been rare reports of myocardial infarction in patients who were treated with repaglinide and isophane insulin; the combination is not recommended. Precautions are similar to those which apply with the shorter-acting sulfonylurea hypoglycaemics. Repaglinide should be given with caution to patients with hepatic impairment (consideration should be given to extending the interval between doses), and possibly avoided in severe impairment.

Effects on the liver.

Hepatotoxic reactions have been reported for repaglinide1,2 including cholestatic hepatitis and jaundice with pruritus.
1. Nan DN, et al. Acute hepatotoxicity caused by repaglinide. Ann Intern Med 2004; 141: 823
2. López-García F, et al. Cholestatic hepatitis associated with repaglinide. Diabetes Care 2005; 28: 752–3.

Fasting.

For mention that nateglinide or repaglinide can probably be used with low risk of hypoglycaemia in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Hypoglycaemia.

Mild hypoglycaemia has been reported in patients receiving repaglinide,1 although in a study comparing flexible repaglinide dosing with fixed glibenclamide dosing, all hypoglycaemic events recorded were in the glibenclamide group.2Other studies have found rates of hypoglycaemia in patients receiving repaglinide to be less than, or similar to, sulfonylureas.3The risk of hypoglycaemia may be reduced as patients can omit a dose of repaglinide if a meal is missed.
1. Moses RG, et al. Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. Diabetes Care 2001; 24: 11–15.
2. Damsbo P, et al. A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. Diabetes Care 1999; 22: 789–94
3. Culy CR, Jarvis B. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 2001; 61: 1625–60.

Pregnancy.

Insulin is generally preferred to oral antidiabetics in the treatment of diabetes mellitus during pregnancy. Repaglinide has been used in 3 women during the first 6 to 7 weeks of gestation;1,2 treatment was then changed to insulin for the rest of the pregnancy. Their babies were delivered at term, with adequate weight for birth age and no congenital malformations.
1. Napoli A, et al. Use of repaglinide during the first weeks of pregnancy in two type 2 diabetic women. Diabetes Care 2006; 29: 2326–7
2. Mollar-Puchades MA, et al. Use of repaglinide on a pregnant woman during embryogenesis. Diabetes Obes Metab 2007; 9: 146–7.

💊 Interactions

As with other oral antidiabetics, the efficacy of repaglinide may be affected by drugs independently increasing or decreasing blood glucose concentrations. Drugs that affect the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 may alter the metabolism of repaglinide. Use of repaglinide with the CYP2C8 inhibitor gemfibrozil has resulted in marked reduction in repaglinide clearance, and severe hypoglycaemia; UK licensed product information contra-indicates concomitant use.
1. Hatorp V, Thomsen MS. Drug interaction studies with repaglinide: repaglinide on digoxin or theophylline pharmacokinetics and cimetidine on repaglinide pharmacokinetics. J Clin Pharmacol 2000; 40: 184–92
2. Hatorp V, et al. Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide. J Clin Pharmacol 2003; 43: 649–60
3. Scheen AJ. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. Clin Pharmacokinet 2007; 46: 93–108.

Antibacterials.

A study1 in healthy subjects found that the plasma concentration of a single dose of repaglinide was reduced, and its half-life shortened, when it was given 12.5 hours after the last dose of a 5-day course of rifampicin. This effect was attributed to the induction of the cytochrome P450 isoenzyme CYP3A4 by rifampicin. In another study2 repaglinide was given either with the last dose of a 7-day course of rifampicin or 24 hours later, and the effects on repaglinide were found to be greater on day 8 than day 7. The authors suggested that rifampicin acted as both an inducer and an inhibitor of CYP3A4 and possibly CYP2C8, and that after rifampicin was stopped its inductive effect lasted longer, thereby having a greater effect 24 hours later. A study3 in healthy subjects reported that clarithromycin can increase the plasma concentrations and prolong the elimination half-life of repaglinide, probably by inhibition of CYP3A4. Telithromycin, another inhibitor of CYP3A4, also increased plasma concentrations of repaglinide in a study of healthy subjects, although the elimination half-life of repaglinide was not significantly affected.4 Trimethoprim5 can have a similar effect by the inhibition of CYP2C8. For a report of hypoglycaemia when gatifloxacin was given to a patient already receiving repaglinide.
1. Niemi M, et al. Rifampin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2000; 68: 495–500
2. Bidstrup TB, et al. Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. Eur J Clin Pharmacol 2004; 60: 109–14
3. Niemi M, et al. The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2001; 70: 58–65
4. Kajosaari LI, et al. Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin Pharmacol Ther 2006; 79: 231–42
5. Niemi M, et al. The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004; 57: 441–7.

Ciclosporin.

Ciclosporin markedly increased plasma concentrations of repaglinide in healthy subjects;1 there is a possibly increased risk of hypoglycaemia if these 2 drugs are taken together.
1. Kajosaari LI, et al. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther 2005; 78: 388–99.

Grapefruit juice.

Grapefruit juice increased the bioavailability of repaglinide in a study of healthy subjects.1 The half-life of repaglinide was not affected, suggesting that grapefruit juice inhibited its presystemic metabolism by the cytochrome P450 isoenzyme CYP3A4 in the gut wall. Blood-glucose concentrations were not affected.
1. Bidstrup TB, et al. The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide. Br J Clin Pharmacol 2006; 61: 49–57.

Lipid regulating drugs.

A study1 in healthy subjects found that gemfibrozil significantly increased the plasma concentrations of repaglinide and enhanced and prolonged its glucoselowering effect. Use of this combination should be avoided. Another study2 in healthy subjects found, however, that repaglinide was not affected by bezafibrate or fenofibrate.
1. Niemi 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: 347–51
2. Kajosaari LI, et al. Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004; 58: 390–6.

💊 Pharmacokinetics

Repaglinide is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 hour. The mean bioavailability is about 60%. Repaglinide is highly bound to plasma proteins, and has a plasma elimination half-life of about 1 hour. It undergoes almost complete hepatic metabolism involving the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. The metabolites, which are inactive, are excreted in the bile. Higher plasma concentrations and prolonged half-life of repaglinide may occur in patients with renal impairment (creatinine clearance less than 40 mL/minute) or chronic liver disease.
1. Hatorp V, et al. Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. J Clin Pharmacol 2000; 40: 142–52
2. Hatorp V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet 2002; 41: 471–83
3. Bidstrup TB, et al. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol 2003; 56: 305–14.

💊 Uses and Administration

Repaglinide is a meglitinide antidiabetic used for the treatment of type 2 diabetes mellitus. It has a chemical structure different from that of the sulfonylureas, but appears to have a similar mode of action. Repaglinide is given up to 30 minutes before meals, in usual initial oral doses of 0.5 mg; initial doses of 1 or 2 mg are usually given to patients who have had previous hypoglycaemic treatment. The dose may be adjusted, at intervals of 1 to 2 weeks, up to a maximum of 4 mg before meals; a total of 16 mg daily should not be exceeded. Repaglinide is also given with metformin or a thiazolidinedione in type 2 diabetes not adequately controlled by monotherapy.
1. Anonymous. Repaglinide for type 2 diabetes mellitus. Med Lett Drugs Ther 1998; 40: 55–6
2. Moses R, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 1999; 22: 119–24
3. Wolffenbuttel BH, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Diabetes Care 1999; 22: 463–7
4. Moses RG, et al. Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. Diabetes Care 2001; 24: 11–15
5. Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001; 358: 1709–16
6. Culy CR, Jarvis B. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 2001; 61: 1625–60
7. Moses R. Repaglinide in combination therapy. Diabetes Nutr Metab 2002; 15 (suppl): 33–8
8. Derosa G, et al. Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors. Clin Ther 2003; 25: 472–84
9. Raskin P, et al. Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone. Diabet Med 2004; 21: 329–35.

Administration in renal impairment.

Although repaglinide is cleared mainly by hepatic metabolism, small pharmacokinetic studies have reported that exposure to repaglinide may be increased in patients with renal impairment.1,2 A larger open-label study3 that included 151 patients with normal renal function and 130 patients with varying degrees of renal impairment found that the incidence of adverse effects was not influenced by renal function. However, at the end of the 3-month maintenance treatment period, there was a trend towards lower effective doses of repaglinide with increasing degree of renal impairment.
1. Marbury TC, et al. Pharmacokinetics of repaglinide in subjects with renal impairment. Clin Pharmacol Ther 2000; 67: 7–15
2. Schumacher S, et al. Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur J Clin Pharmacol 2001; 57: 147–52
3. Hasslacher C. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care 2003; 26: 886–91.

💊 Preparations

USP 31: Repaglinide Tablets.

Proprietary Preparations

Arg.: Glukenil; NovoNorm; Sestrine; Austral.: NovoNorm; Austria: NovoNorm; Belg.: NovoNorm; Braz.: Gluconorm; NovoNorm; Prandin; Canad.: Gluconorm; Chile: Hipover; NovoNorm; Cz.: NovoNorm; Prandin; Denm.: NovoNorm; Fin.: NovoNorm; Fr.: NovoNorm; Ger.: NovoNorm; Gr.: NovoNorm; Hong Kong: NovoNorm; Hung.: NovoNorm; India: Rapilin; Irl.: NovoNorm; Israel: NovoNorm; Ital.: NovoNorm; Malaysia: NovoNorm; Mex.: NovoNorm; Neth.: NovoNorm; Prandin; Norw.: NovoNorm; NZ: NovoNorm; Philipp.: NovoNorm; Pol.: NovoNorm; Port.: NovoNorm; Prandin; Rus.: NovoNorm (НовоНорм); S.Afr.: NovoNorm; Singapore: NovoNorm; Spain: NovoNorm; Prandin; Swed.: NovoNorm; Switz.: NovoNorm; Thai.: NovoNorm; Turk.: NovoNorm; UK: Prandin; USA: Prandin.
Published November 25, 2018.