Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action PrandiMet 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 PrandiMet 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 Treatment N Pharmacokinetic Parameter AUC (ng•h/mL) Cmax (ng/mL) Repaglinide 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) Metformin 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) Treatment: 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. 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 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. Specific Populations Renal Impairment 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. Hepatic Impairment 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. 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 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 Study Drug* Metformin AUC Metformin Cmax Cimetidine 40%↑ 60%↑ Furosemide 15% ↑ 22%↑ Nifedipine 9%↑ 20%↑ Propranolol-metformin 10% ↓ 6% ↓ Ibuprofen-metformin 5%↑ 7%↑ Unless indicated all drug interactions were observed with single dose co-administration *single and multiple dose co-administration ↑indicates increase ↓indicates decrease Table  4 : Effect of Other Drugs on AUC Cmax of Repaglinide Study Drug Dose Other Drug Duration Other Drug Repaglinide AUC Cmax 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 increase ↓indicates decrease * Indicates data are from published literature Table 5: Effect of Metformin or Repaglinide on AUC and Cmax of Other Drugs Other Drugs AUC Cmax Furosemide 1 12% ↓ 31%↓ Ethinyl Estradiol 2 20%↑ 20%↑ Fenofibrate 0% 18%↑ 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. ↓indicates decrease ↑indicates increase 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 Repaglinide add-on to Metformin HCl Repaglinide monotherapy Metformin HCl monotherapy N 27 28 27 Median Final Dose (mg/day) 6 (repaglinide) 1500 (metformin HCl) 12 1500 HbAic (%) Baseline 8.3 8.6 8.6 Change from baseline -1.4* -0.4 -0.3 Fasting plasma glucose (mg/dL) Baseline 184 174 194 Change from baseline -39* +9 -5 Weight (kg) Baseline 93 87 91 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.

PrandiMet® (repaglinide and metformin HCl) Tablets WARNING LACTIC ACIDOSIS Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. If acidosis is suspected, PrandiMet should be discontinued and the patient hospitalized immediately [see WARNINGS AND PRECAUTIONS]. DESCRIPTION PrandiMet (repaglinide and metformin HCl) tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: repaglinide and metformin HCl. The concomitant use of repaglinide and metformin has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on  exercise, diet, and metformin HCl alone. Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues. Repaglinide is a white to off-white powder with molecular formula C27 H36 N2 O4 and a molecular weight of 452.6 with the structural formula as shown below. Repaglinide is freely soluble in methanol and ethanol. The pKa of repaglinide in acid is 3.9, and the pKa in amine is  6.0. Structural formula of Repaglinide Metformin HCl (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula of metformin HCl is: PrandiMet is available as a tablet for oral administration containing 1 mg repaglinide with 500 mg metformin HCl (1 mg/500 mg) or 2 mg repaglinide with 500 mg metformin HCl (2 mg/500 mg) formulated with the following inactive ingredients: poloxamer 188, microcrystalline cellulose, polacrillin potassium, magnesium stearate, hypromellose 3cp or 6cp, povidone, meglumine, sorbitol, talc, titanium dioxide, red or yellow iron oxide, and polyethylene glycol. Propylene glycol is present in the 2 mg/500 mg PrandiMet tablets.

INDICATIONS PrandiMet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin HCl alone. Important Limitations of Use PrandiMet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. DOSAGE AND ADMINISTRATION Recommended Dosing The dosage of PrandiMet should be individualized on the basis of the patient's current regimen, effectiveness and tolerability. PrandiMet can be administered 2 to 3 times a day up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin HCl. No more than 4 mg repaglinide/1000 mg metformin HCl should be taken per meal. Initiation and maintenance of combination therapy with PrandiMet should be individualized to the patient, and at the discretion of the health care provider. Blood glucose monitoring should be performed to determine the therapeutic response to PrandiMet. PrandiMet doses should usually be 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 Inadequately Controlled with Metformin HCl Monotherapy If therapy with a combination tablet containing repaglinide and metformin HCl is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with metformin HCl alone, the recommended starting dose of PrandiMet is 1 mg repaglinide/500 mg metformin HCl administered twice daily with meals, with gradual dose escalation (based on glycemic response) to reduce the risk of hypoglycemia with repaglinide. Patients Inadequately Controlled with Meglitinide Monotherapy If therapy with a combination tablet containing repaglinide and metformin HCl is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with repaglinide alone, the recommended starting dose of the metformin HCl component of PrandiMet should be 500 mg metformin HCl twice a day, with gradual dose escalation (based on glycemic response) to reduce gastrointestinal side effects associated with metformin HCl. Patients Currently Using Repaglinide and Metformin HCl Concomitantly For patients switching from repaglinide co-administered with metformin HCl, PrandiMet can be initiated at the dose of repaglinide and metformin HCl similar to (but not exceeding) the patient's current doses, then may be titrated to the maximum daily dose as necessary to achieve targeted glycemic control. No studies have been performed examining the safety and efficacy of PrandiMet in patients previously treated with other oral antihyperglycemic agents and switched to PrandiMet. Any change in therapy should be undertaken with care and with appropriate monitoring as changes in glycemic control can occur. HOW SUPPLIED Dosage Forms And Strengths 1 mg repaglinide /500mg metformin HCl tablets are yellow, biconvex, debossed with Novo Nordisk (Apis) bull symbol on one side, and strength indicated on the other side 2 mg repaglinide /500mg metformin HCl tablets are pink, biconvex, debossed with Novo Nordisk (Apis) bull symbol on one side, and strength indicated on the other side Storage And Handling PrandiMet tablets are supplied as biconvex tablets available in 1 mg/500 mg (yellow) and 2 mg/500 mg (pink) strengths. Tablets are debossed with the Novo Nordisk (Apis) bull symbol on one side and tablet strength on the other side. The tablets are colored to indicate strength. 1 mg repaglinide/500 mg metformin HCl tablets yellow) Bottles of 20 NDC 0169-0093-21 Bottles of 100 NDC 0169-0093-01 2 mg repaglinide/500 mg metformin HCl tablets pink) Bottles of 20 NDC 0169-0092-21 Bottles of 100 NDC 0169-0092-01 Do not store above 25° C (77° F). Protect from moisture. Keep bottles tightly closed. Dispense in tight containers with safety closures. Manufactured for: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark . For information contact: Novo Nordisk Inc. 100 College Road West Princeton, New Jersey 08540. Revised: 4/2012

PATIENT INFORMATION 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.

SIDE EFFECTS Most Frequently Observed Adverse Reactions Repaglinide In clinical trials of repaglinide, hypoglycemia is the most common adverse reaction (> 5%) leading to withdrawal of patients treated with repaglinide. Metformin HCl 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. Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy 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* Coadministered repaglinide and metformin HCl N (%) Metformin HCl monotherapy N (%) Repaglinide monotherapy N (%) No. of Patients Exposed 27 27 28 Gastrointestinal System Disorder 9 (33) 13 (48) 10 (36) Diarrhea 5 (19) 8 (30) 2 (7) Nausea 4 (15) 2 (7) 1 (4) Symptomatic Hypoglycemia ** 9 (33) 0 (0) 3 (11) Headache 6 (22) 4 (15) 3 (11) Upper Respiratory Tract Infection 3 (11) 3 (11) 3 (11) *Intent to treat population ** There were no cases of severe hypoglycemia (hypoglycemia requiring the assistance of another person) 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 Repaglinide 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. DRUG INTERACTIONS Cationic Drugs Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of PrandiMet and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see CLINICAL PHARMACOLOGY]. CYP2C8 and CYP3A4 Inhibitors/Inducers Repaglinide is metabolized by CYP2C8 and to a lesser extent by CYP3A4. Drugs that inhibit 2C8 (gemfibrozil, trimethoprim, deferasirox), inhibit 3A4 (itraconazole, ketaconazole), or induce CYP2C8/3A4 (rifampin) may alter the pharmacokinetics and pharmacodynamics of repaglinide. In vivo data from a study that evaluated the coadministration of gemfibrozil and repaglinide in healthy subjects showed a significant increase in repaglinide blood levels. Administration of PrandiMet and gemfibrozil to the same patient is not recommended [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Repaglinide exposures are increased more than 20-fold in patients taking both gemfibrozil and itraconazole [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Lactic Acidosis Metformin hydrochloride Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with PrandiMet; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1,000 patient-years of exposure, with approximately 0.015 fatal cases/1,000 patient-years of exposure). In more than 20,000 patient-years exposure to metformin HCl in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking PrandiMet and by use of the minimum effective dose of PrandiMet. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Treatment with PrandiMet should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, PrandiMet should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, PrandiMet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking PrandiMet, since alcohol potentiates the effects of metformin HCl on lactate metabolism. In addition, PrandiMet should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. PrandiMet should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of PrandiMet, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking PrandiMet do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking PrandiMet, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see CONTRAINDICATIONS]. Impaired Renal Function Patients with renal impairment should not receive PrandiMet [see  CONTRAINDICATIONS]. As metformin is substantially excreted by the kidney, before initiation of therapy with PrandiMet and at least  annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of  renal impairment is anticipated, renal function should be assessed more frequently and PrandiMet discontinued if  evidence of renal impairment is present [see CLINICAL PHARMACOLOGY ]. Radiologic Studies with Intravascular Iodinated Contrast Materials Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin HCl [see CONTRAINDICATIONS]. Therefore, in patients in whom any such study is planned, PrandiMet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. Impaired Hepatic Function Hepatic impairment has been associated with some cases of lactic acidosis. Therefore, PrandiMet should generally be avoided in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving PrandiMet. Combination with NPH-insulin Repaglinide Repaglinide is not indicated for use in combination with NPH-insulin. Across seven controlled clinical trials, there were six serious adverse events (1.4%) of myocardial ischemia with repaglinide in combination with NPH-insulin compared to one event (0.3%) in patients using insulin alone [see ADVERSE REACTIONS]. Drug Interactions Repaglinide is partly metabolized by CYP2C8 and CYP3A4 and appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit CYP2C8, CYP3A4, or OATP1B1 (e.g., cyclosporine) may increase plasma concentrations of repaglinide. Dose reduction of repaglinide may be needed [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY ]. Gemfibrozil significantly increased repaglinide exposure. Therefore, patients should not take PrandiMet with gemfibrozil [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. Hypoglycemia Most blood glucose-lowering drugs, including repaglinide, can cause hypoglycemia. Patients who have not previously been treated with a meglitinide should be started on the lowest available repaglinide component of PrandiMet to reduce the risk of hypoglycemia. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs [see ADVERSE REACTIONS]. Vitamin B12 Levels In controlled clinical trials of metformin HCl 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 HCl or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on PrandiMet 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. Surgical Procedures Use of PrandiMet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. Loss of Control of Blood Glucose When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold PrandiMet and temporarily administer insulin. PrandiMet may be reinstituted after the acute episode is resolved. Use of Concomitant Medications Affecting Renal Function or Metformin Disposition Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see DRUG INTERACTIONS] should be used with caution. Hypoxic States Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving PrandiMet, the drug should be promptly discontinued. Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes A patient with type 2 diabetes previously well-controlled on PrandiMet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, PrandiMet must be stopped immediately and other appropriate corrective measures initiated. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PrandiMet or any other oral anti-diabetic drug. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility PrandiMet No animal studies have been conducted with the combined products in PrandiMet 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 HCl 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 HCl component of PrandiMet 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 HCl component of PrandiMet on a mg/m² basis). There was no evidence of a mutagenic potential of metformin HCl 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 HCl 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 HCl component of PrandiMet on a mg/m² basis). Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women with PrandiMet or its individual components. Because animal reproduction studies are not always predictive of human response, PrandiMet like other antidiabetic medications, should be used during pregnancy only if clearly needed. No animal studies have been conducted with the combined products in PrandiMet. 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 HCl Metformin HCl 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 HCl component of PrandiMet based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Nursing Mothers No studies in lactating animals have been conducted with the PrandiMet fixed dose combination. In studies performed with individual components, both repaglinide and metformin are excreted into milk of lactating rats. 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 HCl Studies in lactating rats with metformin HCl show that it is excreted into milk and reaches levels comparable to  those in plasma. It is not known whether repaglinide or metformin are excreted in human milk. PrandiMet is not recommended in nursing mothers because it may potentially cause hypoglycemia in nursing infants. Pediatric Use Safety and effectiveness of PrandiMet in pediatric patients have not been established. PrandiMet is not recommended for use in children. Geriatric Use 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. In patients with advanced age, PrandiMet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, dose adjustment of PrandiMet should be based on a careful assessment of renal function [see WARNINGS AND PRECAUTIONS, CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].