Repaglinide in Pregnancy and Breastfeeding
Risk Factor: CM
Class: Hormones
/ Antidiabetic agents
Fetal Risk Summary
Repaglinide is a nonsulfonylurea oral hypoglycemic agent (meglitinide class) that is used, either alone or in combination with metformin, as an adjunct to diet and exercise in the management of type II diabetes (non-insulin-dependent diabetes mellitus). It is an insulin secretagogue. After absorption from the gastrointestinal tract, repaglinide is rapidly metabolized to inactive metabolites.
In animal reproduction studies, repaglinide was not teratogenic in rats and rabbits at doses 40 and 0.8 times the human clinical exposure based on a body surface area (HCE), respectively (1). However, offspring of rat dams given doses 15 times the HCE in the latter part of gestation and during lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. The no-effect doses were 2.5 times the HCE given throughout pregnancy (through day 22) or higher doses given through gestational day 16 (1). A study published in 2000 found effects similar to those above in pregnant rats (2). Because the toxic effects on long bone development were only observed after organogenesis and only with high doses, the investigators concluded that the toxicity was limited to effects on growth and that repaglinide was not teratogenic (2).
It is not known if repaglinide crosses the human placenta. The molecular weight (about 453) is low enough, however, that transfer to the fetus should be expected.
No reports describing the use of repaglinide during human pregnancy have been located. Insulin is the treatment of choice for pregnant diabetic patients because, in general, other hypoglycemic agents do not provide adequate glycemic control. Moreover, insulin, unlike most oral agents, does not cross the placenta to the fetus, thus eliminating the additional concern that the drug therapy itself will adversely effect the fetus. Carefully prescribed insulin therapy provides better control of the mother's glucose, thereby preventing the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as may occur in diabetes mellitus, are closely associated with a number of maternal and fetal adverse effects, including fetal structural anomalies if the hyperglycemia occurs early in gestation. To prevent this toxicity, most experts, including the American College of Obstetricians and Gynecologists, recommend that insulin be used for types I and II diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (3,4).
Breast Feeding Summary
No reports describing the use of repaglinide during human lactation have been located. The molecular weight (about 453) is low enough that excretion into breast milk should be expected. Consistent with the relatively low molecular weight, repaglinide was detected in the milk of lactating rats (1). Skeletal deformities (see above) were produced in nursing pups who had not been exposed to the drug during gestation (1,2). Because of the unknown potentials for this toxicity and hypoglycemia in a nursing infant, repaglinide should not be used during breast feeding (5).
References
- Product information. Prandin. Novo Nordisk Pharmaceuticals, 2000.
- Viertel B, Guttner J. Effects of the oral antidiabetic repaglinide on the reproduction of rats. Arzneim-Forsch/Drug Res 2000;50:42540.
- American College of Obstetricians and Gynecologists. Diabetes and pregnancy. Technical Bulletin. No. 200, December 1994.
- Coustan DR. Management of gestational diabetes. Clin Obstet Gynecol 1991;34:55864.
-
Guay DRP. Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus. Pharmacotherapy 1998;18:11951204.
Questions and Answers
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About gluconorm (repaglinide) following is the detailed information
Repaglinide is an oral blood glucose-lowering drug used in the management of type 2 diabetes mellitus. Repaglinide is a short-acting insulin secretagogue which lowers blood glucose levels (as measured by HbA 1C and fasting plasma glucose) and is effective in regulating meal-related (prandial) glucose loads. Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.
Repaglinide is chemically unrelated to oral sulphonylurea insulin secretagogues used in the treatment of type 2 diabetes.
Repaglinide closes ATP-dependent potassium channels in the b-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the b-cell which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.
Pharmacokinetics: Absorption: After oral administration, repaglinide is rapidly and completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak drug levels (C max) occur within 1 hour (T max). Repaglinide is rapidly eliminated from the blood stream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean T max was not changed, but the mean C max and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.
Distribution: After i.v. dosing in healthy subjects, the volume of distribution at steady state (V SS) was approximately 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%.
Metabolism: Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an i.v. or oral dose. The major metabolites are an oxidized dicarboxylic acid (M 2), the aromatic amine (M 1) and the acyl glucuronide (M 7). The cytochrome P450 enzyme system, specifically 3A4, has been shown to be involved in the N-dealkylation of repaglinide to M 2 and the further oxidation to M 1. Metabolites do not contribute to the glucose-lowering effect of repaglinide.
Excretion: Within 96 hours after dosing with 14C-repaglinide as a single oral dose, approximately 90% of the radiolabel was recovered in the feces and 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M 2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces.
Pharmacokinetic parameters: Data indicate that repaglinide did not accumulate in serum. Repaglinide demonstrated pharmacokinetic linearity over the 0.5 to 4 mg dose range.
The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a multiple- dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in patients with Type 2 diabetes are summarized in Table I.
Variability: The intraindividual and interindividual variabilities (coefficient of variation) in AUC were 36% and 69%, respectively, after multiple dosing of repaglinide tablets (0.25 to 4 mg with each meal) in patients.
Geriatrics: Healthy volunteers were treated with a regimen of 2 mg taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and a comparably sized group of patients ³65 years of age.
Gender: A comparison of pharmacokinetics in males and females showed the AUC over the 0.5 to 4 mg dose range to be 15 to 70% higher in females with type 2 diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. With respect to gender, no change in general dosage recommendation is indicated since dosage for each patient should be individualized to achieve optimal clinical response.
Race: No pharmacokinetic studies to assess the effects of race have been performed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33).
Clinical: A 4-week, double-blind, placebo-controlled dose-response trial was conducted in patients with type 2 diabetes using doses ranging from 0.25 to 4 mg taken with each of 3 meals. Repaglinide therapy resulted in dose-proportional glucose lowering over the full dose range. Plasma insulin levels increased after meals and reverted toward baseline before the next meal. Most of the fasting blood glucose-lowering effect was demonstrated within 1 to 2 weeks.
In a double-blind, placebo-controlled, 3-month dose titration study, repaglinide or placebo doses for each patient were increased weekly from 0.25 mg through 0.5, 1, and 2 mg to a maximum of 4 mg, until a fasting plasma glucose (FPG) level <8.9 mmol/L was achieved or the maximum dose reached. The dose that achieved the targeted control or the maximum dose was continued to end of study. FPG and 2-hour postprandial glucose (PPG) increased in patients receiving placebo and decreased in patients treated with repaglinide. Differences between the repaglinide- and placebo-treated groups were -3.41 mmol/L (FPG) and -5.78 mmol/L (PPG). The between-group change in HbA 1C, which reflects long-term glycemic control, was 1.7% units. See Table II.
Another double-blind, placebo-controlled trial was carried out in 362 patients treated for 24 weeks. The efficacy of 1 and 4 mg preprandial doses was demonstrated by lowering of fasting blood glucose and by HbA 1C at the end of the study. HbA 1C for the repaglinide-treated groups (1 and 4 mg groups combined) at the end of the study was decreased compared to the placebo-treated group in previously naïve patients and in patients previously treated with oral hypoglycemic agents by 2.1% units and 1.7% units, respectively. In this fixed-dose trial, patients who were naïve to oral hypoglycemic agent therapy and patients in relatively good glycemic control at baseline (HbA 1C below 8%) showed greater blood glucoselowering including a higher frequency of hypoglycemia. Patients who were previously treated and who had baseline HbA 1C ³ 8% reported hypoglycemia at the same rate as patients randomized to placebo. There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to repaglinide. The average weight gain in patients treated with repaglinide and not previously treated with sulfonylurea drugs was 3.3%.
The dosing of repaglinide relative to meal-related insulin release was studied in 3 trials including 58 patients. Glycemic control was maintained during a period in which the meal and dosing pattern was varied (2, 3, or 4 meals/day; before meals x 2, 3, or 4) compared with a period of 3 regular meals and 3 doses/day (before meals x 3). It was also shown that repaglinide can be administered at the start of a meal, 15 minutes before, or 30 minutes before the meal with the same blood glucose lowering effect.
Repaglinide was compared to other insulin secretagogues in 1-year controlled trials to demonstrate comparability of efficacy and safety. Hypoglycemia was reported in 16% of 1 228 repaglinide patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients. Of repaglinide-treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization.
Indications: As an adjunct to diet and exercise to lower the blood glucose in patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled satisfactorily by diet and exercise alone.
Repaglinide is also indicated for use in combination with metformin to lower blood glucose in patients whose hyperglycemia cannot be controlled by exercise, diet, and either repaglinide or metformin alone. If glucose control has not been achieved after a suitable trial of combination therapy, consideration should be given to discontinuing these drugs and using insulin. Judgments should be based on regular clinical and laboratory evaluations.
In initiating treatment for type 2 diabetes, diet and exercise should be emphasized as the primary form of treatment. Caloric restriction, weight loss and exercise are essential in the obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken where possible.
If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral blood glucose-lowering agent or insulin should be considered. Use of repaglinide must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may
