Tag Archives: NovoNorm
Current Oral Antidiabetic Therapy: Benzoic Acid Derivatives
Repaglinide
Brand Name Drug: Prandin in the U.S., GlucoNorm in Canada, NovoNorm elsewhere
Benzoic acid derivatives are the most recent addition to the list of treatment options for type 2 diabetes. In 1998, the FDA approved the first agent in this class, repaglinide. Benzoic acid derivatives are similar to sulfonylureas in that they are insulin secretagogues. However, they differ in that they bind to a different receptor on the beta cell membrane. Also, in contrast to sulfonylureas, benzoic acid derivatives do not cause direct exocytic insulin release in the absence of glucose stimulation.
The true benefit of these agents stems from the fact that they have a short duration of action. Repaglinide is administered just before the start of the meal and stimulates insulin secretion. However, the duration of action is much shorter than the sulfonylureas, and the main effect is to reduce postprandial hyperglycemia. Due to the short half-life, repaglinide is useful in patients who have erratic meal schedules.
The main advantage of repaglinide is the potential for decreased incidence of hypoglycemia, making it an effective agent in elderly patients and those with renal insufficiency or other predisposition to hypoglycemia. It is given only at the meal time in 1-mg and 2-mg tablets. Most patients are started on 0.5 mg prior to meals. It often is useful to initially monitor pre- and one-hour postprandial fingerstick glucoses to assess the effects of this agent.
Conclusion
Much of the benefit from tight control in patients with type 1 diabetes has now been extrapolated to the much larger group of patients with type 2 diabetes. Recent data have shown that tight control of type 2 diabetes is strongly associated with a decreased incidence and rate of progression of microvascular complications. Multiple new oral agents recendy have been developed for the treatment of this disorder. Effective use of these agents by physicians is imperative in controlling this disease and preventing or delaying acute and chronic complications in African Americans. It is important to remember that these new agents are relatively ineffective without proper dietary counseling and increased physical activity. In addition to glycemic control, treatment of hypertension and hyperlipidemia will also result in significant decreases in micro- and macrovascular disease in individuals with type 2 diabetes.
Comprehensive screening also is essential as it is estimated that 50% of Americans with the disease are unaware of their illness. The ADA now recommends testing of fasting glucose every three years for all adults >45 years. For higher risk groups, such as African Americans and those with a history of gestational diabetes, screening is recommended on a yearly basis. Those patients with a fasting glucose >126 mg/dL must receive proper dietary and exercise instruction as well as diabetic teaching about the importance of foot care and home glucose monitoring. These measures combined with the effective use of pharmacologic agents in those who fail conservative therapy will improve the control of the type 2 diabetes epidemic in the black community.
Repaglinide
Drug Approvals
(British Approved Name, US Adopted Name, rINN)
Pharmacopoeias. In Europe and US.
European Pharmacopoeia, 6th ed. (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.
The United States Pharmacopeia 31, 2008 (Repaglinide). A white to off-white solid. Solubleinme-thyl 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 repaglinide’ including cholestatic hepatitis and jaundice with pruritus.
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, although in a study comparing flexible repaglinide dosing with frxed glibenclamide dosing, all hypoglycaemic events recorded were in the glibenclamide group.Other studies have found rates of hypoglycaemia in patients receiving repaglinide to be less than, or similar to, sulfonylureas.The risk of hypoglycaemia may be reduced as patients can omit a dose of repaglinide if a meal is missed.
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 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.
Interactions
As with other oral antidiabetics, the efficacy of repaglinide may be affected by drugs independently increasing or decreasing blood glucose concentrations (see Sulfonylureas).
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.
Antibacterials. A study 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 ofrifampicin. This effect was attributed to the induction of the cytochrome P450 isoenzyme C YP3A4 by rifampicin. In another study 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 C YP3 A4 and possibly C YP2C8, and that after rifampicin was stopped its inductive effect lasted longer, thereby having a greater effect 24 hours later. A study 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. Trimethoprim 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.
Ciclosporin. Ciclosporin markedly increased plasma concentrations of repaglinide in healthy subjects there is a possibly increased risk of hypoglycaemia if these 2 drugs are taken together.
Grapefruit juice. Grapefruit juice increased the bioavailability of repaglinide in a study of healthy subjects. 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.
Lipid regulating drugs. A study in healthy subjects found that gemfibrozil significantly increased the plasma concentrations of repaglinide and enhanced and prolonged its glucose-lowering effect. Use of this combination should be avoided. Another study in healthy subjects found, however, that repaglinide was not affected by bezafibrate or fenofibrate.
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.
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 maybe 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.
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. A larger open-label study 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.
Preparations
The United States Pharmacopeia 31, 2008: Repaglinide Tablets.
Proprietary Preparations
Argentina: Glukenil NovoNorm Sestrine
Australia: NovoNorm
Austria: NovoNorm
Belgium: NovoNorm
Brazil: Gluconorm NovoNorm Prandin
Canada: Gluconorm
Chile: Hipover NovoNorm
Czech Republic: NovoNorm Prandin
Denmark: NovoNorm
Finland: NovoNorm
France: NovoNorm
Germany: NovoNorm
Greece: NovoNorm
Hong Kong: NovoNorm
Hungary: NovoNorm
India: Rapilin
Ireland: NovoNorm
Israel: NovoNorm
Italy: NovoNorm
Malaysia: NovoNorm
Mexico: NovoNorm
The Netherlands: NovoNorm Prandin
Norway: NovoNorm
New Zealand: NovoNorm
Philippines: NovoNorm
Poland: NovoNorm
Portugal: NovoNorm Prandin
Russia: NovoNorm
South Africa: NovoNorm
Singapore: NovoNorm
Spain: NovoNorm Prandin
Sweden: NovoNorm
Switzerland: NovoNorm
Thailand: NovoNorm
Turkey: NovoNorm
UK: Prandin
USA: Prandin
Prandin (Repaglinide): An Investigational Drug For Diabetes
Repaglinide (Prandin in the U.S., GlucoNorm in Canada, NovoNorm elsewhere) belongs to a new chemical class of drugs called insulin secreting agents; it acts by causing a rapid and short-lived release of insulin by the body. The potential impact of matching insulin release to meal intake was tested along with the ability of this new drug to improve the control. of blood sugar levels Eighteen patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) were divided into 2 groups. The group designated REP3 received repaglinide 3 time daily before meals, and REP2 received the same dosage given twice daily, both for a total of 4 weeks. The REP3 group was given 0.25 mg before breakfast, lunch and dinner, while the REP2 group was given 0.50 mg before breakfast, a placebo before lunch, and 0.25 mg before dinner. Doses were doubled after 2 weeks.
After 4 weeks, fasting blood glucose levels decreased significantly in both groups; 11.2 to 9.6 mmol/L in REP2, and 11.2 to 8.4 mmol/L in the REP3 group. The overall glycemic control was better in REP3 when compared to REP2, as blood glucose was 8.91 mmol/L in REP2 and 7.00 mmol/L in REP3. There was also a significant decrease in HbA1c levels in REP3 (7.5 to 6.5%) but a non-significant decrease in REP2 (7.1 to 6.8%). In both groups plasma insulin decreased to pre-treatment levels prior to the next meal and there was no increase in plasma insulin during the night time in comparison to pre-treatment levels.
Although these are just preliminary findings, they suggest that drugs of this class, can have a beneficial effect on blood sugar control in persons with diabetes.