"The European Medicines Agency (EMA) is alerting doctors and other healthcare professionals to the possibility of atypical cases of diabetic ketoacidosis (DKA) associated with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, a relatively "...
Mechanism of Action
PrandiMet combines two anti-hyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes.
Repaglinide closes ATP-dependent potassium channels in the β-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-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.
Metformin is an anti-hyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes by lowering both the basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
The results of a bioequivalence study in healthy subjects (Table 2) demonstrated that PrandiMet (repaglinide/metformin HCl) 1 mg/500 mg and 2 mg/500 mg combination tablets are bioequivalent to coadministration of corresponding doses of repaglinide and metformin HCl as individual tablets. Repaglinide dose proportionality was demonstrated for PrandiMet (2 mg/500 mg) and PrandiMet (1 mg/500 mg).
Table 2: Mean (SD) Pharmacokinetic Parameters for Repaglinide and
|AUC (ng•h/mL)||Cmax (ng/mL)|
|A||55||34.5 (13.3)||26.0 (13.7)|
|B||55||35.0 (13.2)||23.7 (12.5)|
|C||55||17.6 (6.6)||12.9 (6.9)|
|A||55||6041.9 (1494.6)||838.8 (210.2)|
|B||55||5871.6 (1352.6)||805.9 (160.3)|
|C||55||5948.9 (1442.0)||799.4 (174.6)|
A = 2 mg/500 mg PrandiMet tablet
B = 2 mg repaglinide tablet + 500 mg metformin HCl tablet
C = 1 mg/500 mg PrandiMet tablet
Absorption and Bioavailability
Repaglinide: After single and multiple oral doses in healthy subjects or in patients with type 2 diabetes, peak plasma drug levels (Cmax) occur within 1 hour (Tmax). Repaglinide is 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 Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.
Metformin HCl: The absolute bioavailability of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin HCl tablets of 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration (Cmax), a 25% lower area under plasma concentration (AUC) and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin HCl with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Repaglinide: After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%.
Metformin HCl: The apparent volume of distribution (V/F) of metformin following single oral dose of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin HCl, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 μg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism and Elimination
Repaglinide: Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an intravenous or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide. Within 96 hours after dosing with 14C-repaglinide as a single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces. Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1).
Metformin HCl: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively). Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance.
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
PrandiMet should be avoided in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].
A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: 91.6 ng/mL*hr; AUCCLD patients: 368.9 ng/mL*hr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Patients with impaired liver function may be exposed to higher concentrations of repaglinide and its associated metabolites than would patients with normal liver function receiving usual doses. Therefore, repaglinide should generally be avoided in patients with impaired liver function.
No pharmacokinetics studies with metformin HCl have been conducted in patients with hepatic impairment.
Healthy volunteers treated with repaglinide 2 mg before each of 3 meals, showed no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and those ≥65 years of age.
Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see WARNINGS AND PRECAUTIONS].
Table 3: Effect of Other Drugs on AUC and Cmax of Metformin
|Study Drug*||Metformin AUC||Metformin Cmax|
|Propranolol-metformin||10% ↓||6% ↓|
|Unless indicated all drug interactions were observed with single dose
*single and multiple dose co-administration
Table 4 : Effect of Other Drugs on AUC Cmax of Repaglinide
|Study Drug||Dose Other Drug||Duration Other Drug||Repaglinide|
|Clarithromycin*||250 mg BID||4 days||40%↑||67% ↑|
|Cyclosporine||100 mg 5||1 day||2.5 fold↑||1.8 fold↑|
|Deferasirox*||30 mg/kg QD 6||4 days||2.3 fold↑||62%↑|
|Fenofibrate||200 mg QD||5 days||0%||18% ↑|
|Gemfibrozil*1||600 mg BID||3 days||8.1 fold↑||2.4 fold ↑|
|Itraconazole*||100 mg BID||3 days||1.4 fold↑||1.5 fold ↑|
|Gemfibrozil + Itraconazole Co-administration*1||Gem: 600 mg BID; Itra: 100 mg BID||3 days||19 fold↑||2.8 fold ↑|
|Ketoconazole2||200 mg QD||4 days||15%↑||16%↑|
|Levonorgestrel/ethinyl Estradiol 3||(0.15 mg/0.03 mg) Combination tablet QD||21 days||1.4% ↓||20%↑|
|Nifedipine*3||10 mg TID||4 days||10%↓||5%↓|
|Rifampin*4||600 mg QD||6 - 7 days||32 - 80% ↓||17 - 79%↓|
|Simvastatin3||20 mg QD||4 days||2%↑||26%↑|
|Trimethoprim*||160 mg BID||3 days||61%↑||41%↑|
|Unless indicated all drug interactions were observed with single dose
of 0.25 mg repaglinide
1Coadministration of gemfibrozil with PrandiMet is not recommended [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS ]
2Single dose of 2 mg repaglinide was administered
32 mg repaglinide was administered TID for 4 days
4Single dose of 4 mg repaglinide was administered
5Two doses, twelve hours apart, healthy volunteers
6Single dose of 0.5 mg repaglinide was administered
* Indicates data are from published literature
Table 5: Effect of Metformin or Repaglinide on AUC and Cmax of Other
|Furosemide 1||12% ↓||31%↓|
|Ethinyl Estradiol 2||20%↑||20%↑|
|1When administered with metformin
2Co-administration of a combination tablet (0.15 mg levonorgestrel/0.03 mg ethinyl estradiol) once daily for 21 days with 2 mg repaglinide administered TID (days 1-4) and a single dose on day 5.
Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy
In a double-blind, clinical trial, 83 patients with type 2 diabetes and inadequate glycemic control on metformin HCl monotherapy were randomized to add-on repaglinide, repaglinide monotherapy, or continued treatment with metformin HCl monotherapy. The repaglinide dosage was titrated for 4 to 8 weeks, followed by a 3-month dose maintenance period. Repaglinide add-on to metformin HCl resulted in a statistically significant improvement in HbA1c and fasting plasma glucose compared to the monotherapy arms (Table 6). In this study where metformin HCl dosage was kept constant, repaglinide add-on to metformin HCl resulted in a greater reduction in HbA1c and fasting plasma glucose at a lower daily repaglinide dosage than in the repaglinide monotherapy group (dose sparing with respect to repaglinide). However, the repaglinide add-on to metformin HCl group had a higher incidence of hypoglycemia than the repaglinide monotherapy group [see ADVERSE REACTIONS]. The 2 repaglinide treatment arms experienced weight gain, whereas the metformin HCl monotherapy arm had weight loss.
Table 6: Repaglinide as Add-on to Metformin HCl: Mean Changes from Baseline in Glycemic Parameters and Body Weight After 4 to 5 Months of
|Repaglinide add-on to Metformin HCl||Repaglinide monotherapy||Metformin HCl monotherapy|
|Median Final Dose (mg/day)||6 (repaglinide) 1500 (metformin HCl)||12||1500|
|Change from baseline||-1.4*||-0.4||-0.3|
|Fasting plasma glucose (mg/dL)|
|Change from baseline||-39*||+9||-5|
|Change from baseline||2.4#||3.0||-0.9|
|1 based on intent-to-treat analysis
*: p< 0.05, for pairwise comparisons with repaglinide and metformin HCl monotherapy.
#: p< 0.05, for pairwise comparison with metformin HCl monotherapy.
Last reviewed on RxList: 5/7/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Prandimet Information
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