Repaglinide and Metformin HCl Tablets

Included as part of the PRECAUTIONS section.

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 lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets.

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.

Pharmacokinetics

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 Metformin

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.

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.

Specific Populations

PrandiMet

Because PrandiMet contains metformin HCl, it should not be used in patients with renal impairment [see CONTRAINDICATIONS ; WARNINGS AND PRECAUTIONS].

Repaglinide

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.

Metformin HCl

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

PrandiMet should be avoided in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].

Repaglinide

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.

Metformin HCl

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].

Drug Interactions

Table 3: Effect of Other Drugs on AUC and Cmax of Metformin

Table  4 : Effect of Other Drugs on AUC Cmax of Repaglinide

Table 5: Effect of Metformin or Repaglinide on AUC and Cmax of Other Drugs

Clinical Studies

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 Treatment1

Physician Instructions

Patients should be informed of the potential risks and advantages of PrandiMet and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, HbA1c, renal function, and hematologic parameters. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development and concomitant administration of other glucose-lowering drugs should be explained to patients and family members. Medication requirements may change during periods of stress such as fever, trauma, infection, or surgery, due to loss of glycemic control. Patients should be advised to seek medical advice promptly.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS AND PRECAUTIONS, should be explained to patients. Patients should be advised to discontinue PrandiMet immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of PrandiMet, gastrointestinal symptoms, which are common during initiation of metformin HCl therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be instructed to take PrandiMet with meals. Doses are usually taken within 15 minutes prior to the meal but the timing can vary from immediately preceding the meal up to 30 minutes before the meal. Patients who skip a meal should be instructed to skip the PrandiMet dose for that meal.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving PrandiMet.

Laboratory Tests

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. Vitamin B12 deficiency should be excluded if megaloblastic anemia is detected.

Metformin and repaglinide are oral diabetes medications that help control blood sugar levels. Repaglinide works by causing the pancreas to produce insulin. Metformin works by decreasing glucose (sugar) production in the liver and decreasing absorption of glucose by the intestines.

The combination of metformin and repaglinide is used together with diet and exercise to treat type 2 diabetes.

Metformin and repaglinide may also be used for other purposes not listed in this medication guide.

Some people develop a life-threatening condition called lactic acidosis while taking metformin. You may be more likely to develop lactic acidosis if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your individual risk.

You should not use this medication if you are allergic to metformin (Glucophage) or repaglinide (Prandin), or if you have:

• type 1 diabetes;
• kidney disease;
• if you also use gemfibrozil (Lopid) or NPH insulin (such as isophane insulin); or
• if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and repaglinide.

To make sure you can safely take this medication, tell your doctor if you have any of these other conditions:

• liver disease; or
• a history of heart disease.

FDA pregnancy category C. It is not known whether metformin and repaglinide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication..

It is not known whether metformin and repaglinide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using metformin and repaglinide.

Most Frequently Observed Adverse Reactions

In clinical trials of repaglinide, hypoglycemia is the most common adverse reaction (> 5%) leading to withdrawal of patients treated with repaglinide.

Gastrointestinal reactions (e.g., diarrhea, nausea, vomiting) are the most common adverse reactions (> 5%) with metformin HCl treatment and are more frequent at higher metformin HCl doses.

Clinical Trial Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 summarizes the most common adverse reactions occurring in a 6-month randomized study of repaglinide added to metformin HCl in patients with type 2 diabetes inadequately controlled on metformin HCl alone.

Table 1: Repaglinide added to metformin HCl in patients with type 2 diabetes inadequately controlled on metformin HCl alone. Adverse reaction reported (regardless of Investigator Assessment of Causality) in ≥10% of patients receiving combination therapy*

Cardiovascular Events in repaglinide monotherapy trials

In one-year trials comparing repaglinide to sulfonylurea drugs, the incidence of angina was 1.8% for both treatments, with an incidence of chest pain of 1.8% for repaglinide and 1.0% for sulfonylureas. The incidence of other selected cardiovascular events (hypertension, abnormal electrocardiogram, myocardial infarction, arrhythmias, and palpitations) was ≤ 1% and not different between repaglinide and the comparator drugs.

The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in controlled clinical trials. In 1-year controlled trials, repaglinide treatment was not associated with excess mortality when compared to the rates observed with other oral hypoglycemic agent therapies such as glyburide and glipizide.

Seven controlled clinical trials included repaglinide combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or repaglinide plus metformin HCl) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with repaglinide plus NPH-insulin (1.4%) from two studies, and one event in patients using insulin formulations alone from another study (0.3%) [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of repaglinide. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure.

Postmarketing experience with repaglinide includes infrequent reports of the following adverse events; alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.

Read the entire FDA prescribing information for Prandimet (Repaglinide and Metformin HCl Tablets)