2.1 Recommended Dosage and Administration

General Dosage and Administration information

Administer repaglinide and metformin hydrochloride tablets orally 2 to 3 times a day with meals up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin. No more than 4 mg repaglinide/1000 mg metformin should be taken per meal.

Instruct patients to take repaglinide and metformin hydrochloride tablets within 30 minutes before meals. In patients who skip meals, instruct patients to skip the scheduled dose of repaglinide and metformin hydrochloride tablets to reduce the risk of hypogylcemia. In patients who experience hypoglycemia, the dose of repaglinide should be reduced [see WARNINGS AND PRECAUTIONS (5.2)].

Patients Inadequately Controlled with Metformin Monotherapy

The recommended starting dose of repaglinide and metformin hydrochloride tablets 1 mg repaglinide/500 mg metformin twice daily with meals. Gradually increase dose based on glycemic response to reduce the risk of hypoglycemia with repaglinide.

Patients Inadequately Controlled with Glinide Monotherapy

The recommended starting dose of metformin component of repaglinide and metformin hydrochloride tablets is 500 mg metformin twice daily with meals. Gradually increase dose based on glycemic response to reduce gastrointestinal side effects associated with metformin.

Patients Currently Using Repaglinide and Metformin Concomitantly

Initiate repaglinide and metformin hydrochloride tablets at the dose of repaglinide and metformin similar to (but not exceeding) the patient's current doses. Titrate as needed to achieve glycemic control up to the maximum daily dose.

2.2 Recommended Dosage for Patients with Renal Impairment

Assess renal function with an estimated glomerular filtration rate (eGFR) prior to initiation of repaglinide and metformin hydrochloride tablets and periodically thereafter.

Repaglinide and metformin hydrochloride tablets is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2.

Initiation of repaglinide and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m2 is not recommended.

In patients taking repaglinide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit-risk of continuing therapy.

Discontinue repaglinide and metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1)].

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue repaglinide and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart repaglinide and metformin hydrochloride tablets if renal function is stable [See WARNINGS AND PRECAUTIONS (5.1)].

2.4 Dose Modifications for Drug Interactions

Concomitant use with gemfibrozil is contraindicated [see CONTRAINDICATIONS (4)].

Avoid concomitant use of repaglinide and metformin hydrochloride tablets with clopidogrel. If concomitant use can not be avoided, initiate repaglinide at 0.5 mg before each meal. Although repaglinide and metformin hydrochloride tablets are not available in that strength, repaglinide

0.5 mg tablets are available. Do not exceed a total daily dose of 4 mg of repaglinide [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

Do not exceed a total daily dose of 6 mg of repaglinide in patients receiving cyclosporine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

Dosage adjustments are recommended in patients taking concomitant strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

5.1 Lactic Acidosis

There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.

Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of repaglinide and metformin hydrochloride tablets.

In repaglinide and metformin hydrochloride tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue repaglinide and metformin hydrochloride tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment 

The post-marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see CLINICAL PHARMACOLOGY (12.3)]:

• Before initiating repaglinide and metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR).
• Repaglinide and metformin hydrochloride tablets is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2[see CONTRAINDICATIONS (4)].
• Initiation of repaglinide and metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m2.
• Obtain an eGFR at least annually in all patients taking repaglinide and metformin hydrochloride tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking repaglinide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

Drug Interactions

The concomitant use of repaglinide and metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see DRUG INTERACTIONS (7)]. Therefore, consider more frequent monitoring of patients. 

Age 65 or Greater

The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see USE IN SPECIFIC POPULATIONS (8.5)].

Radiological Studies with Contrast 

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop repaglinide and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart repaglinide and metformin hydrochloride tablets if renal function is stable. 

Surgery and Other Procedures 

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Repaglinide and metformin hydrochloride tablets should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue repaglinide and metformin hydrochloride tablets.

Excessive Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving repaglinide and metformin hydrochloride tablets.

Hepatic Impairment

Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of repaglinide and metformin hydrochloride tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Hypoglycemia

All glinides, including repaglinide and metformin hydrochloride tablets, can cause hypoglycemia [see ADVERSE REACTIONS (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see DRUG INTERACTIONS (7)], or in patients who experience recurrent hypoglycemia.

Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to co-administered medication [see DRUG INTERACTIONS (7)], and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see USE IN SPECIFIC POPULATIONS (8.6, 8.7)].

Patients should administer repaglinide and metformin hydrochloride tablets before meals and be instructed to skip the dose of repaglinide and metformin hydrochloride tablets if a meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide and metformin hydrochloride tablets should be reduced [see DOSAGE AND ADMINISTRATION (2.1)]. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.3 Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. This finding, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on repaglinide and metformin hydrochloride tablets and any apparent abnormalities should be appropriately investigated and managed.

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3- year intervals may be useful.

5.4 Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin

Across seven controlled trials, there were six serious adverse events of myocardial ischemia in patients treated with repaglanide plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [see ADVERSE REACTIONS (6.1)]. repaglinide and metformin hydrochloride tablets is not indicated for use in combination with NPH-insulin.

5.5 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide and metformin hydrochloride tablets.

6.1 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 clinical practice.

Repaglinide and metformin hydrochloride tablets was administered to 374 patients with type 2 diabetes during clinical trials. Table 1 summarizes the most common adverse reactions occurring in a 6-month randomized trial of repaglinide as add-on therapy to metformin in patients inadequately controlled on metformin alone.

Hypoglycemia

In clinical trials with repaglinide, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of repaglinide treated patients and 7% of placebo treated patients.

Gastrointestinal Adverse Reactions

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

Weight Gain

In a clinical trial, 83 patients were randomized to add-on repaglinide, repaglinide monotherapy, or continued treatment with metformin monotherapy. A statistically significant weight gain was observed for the combination of repaglinide and metformin in a pairwise comparison with metformin monotherapy (see Table 2).

Cardiovascular Events in repaglinide monotherapy trials

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.

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 ) (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 (5.4)].

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use. 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.

Repaglinide

Alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

8.1 Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women with repaglinide and metformin hydrochloride tablets or its individual components. Because animal reproduction studies are not always predictive of human response, repaglinide and metformin hydrochloride tablets like other antidiabetic medications, should be used during pregnancy only if clearly needed.

No animal studies have been conducted with the combined products in repaglinide and metformin hydrochloride tablets. The following data are based on findings in studies performed with repaglinide or metformin individually.

Repaglinide

Repaglinide was not teratogenic in rats at doses 40 times, and rabbits approximately 0.8 times the clinical exposure (on a mg/m2 basis) throughout pregnancy. Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of repaglinide administration throughout pregnancy or lactation cannot be established.

Metformin

Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of approximately two and six times the near-maximal efficacious human daily dose of 2000 mg of the metformin component of repaglinide and metformin hydrochloride tablets based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

8.3 Nursing Mothers

No studies in lactating animals have been conducted with the repaglinide and metformin hydrochloride tablets fixed dose combination. In studies performed with individual components, both repaglinide and metformin are excreted into milk of lactating rats. It is not known whether repaglinide or metformin are excreted in human milk. Repaglinide and metformin hydrochloride tablets are not recommended in nursing mothers because it may potentially cause hypoglycemia in nursing infants.

Repaglinide

In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero.

Metformin

Studies in lactating rats with metformin show that it is excreted into milk and reaches levels comparable to those in plasma.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients. [see WARNINGS AND PRECAUTIONS (5.1), CONTRAINDICATIONS (4), CLINICAL PHARMACOLOGY (12.3)].

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Repaglinide and metformin hydrochloride tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. [see DOSAGE AND ADMINISTRATION (2.2), CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1) and CLINICAL PHARMACOLOGY (12.3)]

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Repaglinide and metformin hydrochloride tablets is not recommended in patients with hepatic impairment. [see WARNINGS AND PRECAUTIONS (5.1)]

12.1 Mechanism of Action

Repaglinide and Metformin Hydrochloride Tablets

Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (β) 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 β -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 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.

12.3 Pharmacokinetics

Repaglinide and Metformin Hydrochloride Tablets

The pharmacokinetic profiles of repaglinide and metformin from repaglinide and metformin hydrochloride tablets doses are listed in Table 4 below. The results of a pharmacokinetic

single-dose crossover study in healthy subjects demonstrated that repaglinide has dose proportional pharmacokinetics (AUC and Cmax) for the combination of repaglinide/metformin in repaglinide and metformin hydrochloride tablets (2 mg/500 mg and 1 mg/500 mg).

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

The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin 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 with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution:

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

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, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/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

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:

Renal Impairment

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 to 80 mL/min), and severe renal function impairment (CrCl = 20 to 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:

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1)].

Hepatic Impairment

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.

Metformin:

No pharmacokinetics studies with metformin have been conducted in patients with hepatic impairment.

Geriatric Patients

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 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 (5.1)].

Drug Interactions:

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Repaglinide and Metformin Hydrochloride Tablets

No animal studies have been conducted with the combined products in repaglinide and metformin hydrochloride tablets to evaluate carcinogenesis, mutagenesis and impairment of fertility. The following data are based on findings in studies performed with the individual components.

Repaglinide

In a 104-week carcinogenicity study in rats at doses up to 120 mg/kg/day, the incidences of benign adenomas of the thyroid and liver were increased in male rats. The higher incidences of thyroid and liver tumors in male rats were not seen at lower dose of 30 mg/kg/day and 60 mg/kg/day respectively (which are over 15 and 30 times, respectively, clinical exposures on a mg/m2 basis).

In a 104-week carcinogenicity study in mice at doses up to 500 mg/kg/day, no evidence of carcinogenicity was found in mice (which is approximately 125 times clinical exposure on a mg/m2 basis).

Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver, and in vivo mouse and rat micronucleus tests.

In a rat fertility study, repaglinide was administered to male and female rats at doses up to 300 and 80 mg/kg/day, respectively. No adverse effects on fertility were observed (which are over 40 times clinical exposure on a mg/m2 basis).

Metformin

In a 104-week carcinogenicity study in rats at doses up to 900 mg/kg/day, the incidences of benign stromal uterine polyps were increased in female rats at 900 mg/kg/day (which is approximately four times the maximal recommended human daily dose of 2000 mg of metformin component of repaglinide and metformin hydrochloride tablets on a mg/m2 basis).

In a 91-week carcinogenicity study in mice at doses up to 1500 mg/kg/day, no evidence of carcinogenicity was found in mice (which is approximately four times the maximal recommended human daily dose of 2000 mg of metformin component of repaglinide and metformin hydrochloride tablets on a mg/m2 basis).

There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

In a rat fertility study, metformin was administered to male and female rats at doses up to 600 mg/kg/day. No adverse effects on fertility were observed (which is approximately three times the maximal recommended human daily dose of 2000 mg of metformin component of repaglinide and metformin hydrochloride tablets on a mg/m2basis).

14.1 Repaglinide as Add-on Combination Therapy With Metformin

A total of 83 patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy were randomized to repaglinide as add-on therapy to metformin, repaglinide monotherapy, or continued treatment with metformin monotherapy. The repaglinide dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance period. Combination therapy with repaglinide and metformin resulted in a statistically significant improvement in HbA1c and fasting plasma glucose (FPG) compared to repaglinide or metformin monotherapy (Table 8). In this study where metformin dosage was kept constant, the combination therapy of repaglinide and metformin showed dose-sparing effects with respect to repaglinide. The improvement in HbA1c and FPG of the combination group was achieved at a lower daily repaglinide dosage than in the repaglinide monotherapy group.