ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reaction (incidence 5%) was rash. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. EXTRANEAL was originally studied in controlled clinical trials of 493 patients with end-stage renal disease who received single daily exchange of EXTRANEAL for the long dwell (8-to 16- hours). There were 215 patients exposed for at least months and 155 patients exposed for at least one year. The population was 18-83 years of age, 56% male and 44% female, 73% Caucasian, 18% Black, 4% Asian, 3% Hispanic, and it included patients with the following comorbid conditions: 27% diabetes, 49% hypertension and 23% hypertensive nephropathy.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide basis for identifying the adverse events that appear to be related to drug use and for approximating rates.Rash was the most frequently occurring EXTRANEAL-related adverse reaction (5.5%, EXTRANEAL; 1.7% Control). Seven patients on EXTRANEAL discontinued treatment due to rash, and one patient on EXTRANEAL discontinued due to exfoliative dermatitis. The rash typically appeared within the first three weeks of treatment and resolved with treatment discontinuation or, in some patients, with continued treatment.Table shows the adverse events reported in these clinical studies regardless of causality, occurring in >= 5% of patients and more common on EXTRANEAL than control.Table - Adverse Experiences in >=5% of Patients and More Common on EXTRANEAL EXTRANEALControlN 493N 347Peritonitis26%25%Upper respiratory infection15%13%Hypertension13%8%Rash10%5%Headache9%7%Abdominal Pain8%6%Flu syndrome7%6%Nausea7%5%Cough increase7%4%Edema6%5%Accidental injury6%4%Chest pain5%4%Dyspepsia5%4%Hyperglycemia5%4%Adverse events related to EXTRANEAL use or in conjunction with performing the peritoneal dialysis procedure include:Reported with an incidence of 5% and at least as common on dextrose control included asthenia, exit site infection, infection, back pain, hypotension, diarrhea, vomiting, anemia, peripheral edema, hypokalemia, hyperphosphatemia, hypoproteinemia, hypervolemia, arthralgia, dizziness, dyspnea, pruritis. Reported with an incidence of 5%: pain on infusion, abdominal enlargement, cloudy effluent, ultrafiltration decrease, postural hypotension, heart failure, hyponatremia, hypochloremia, hypercalcemia, hypoglycemia, alkaline phosphatase increase, SGPT increase, SGOT increase, cramping, confusion, lung edema, facial edema, exfoliative dermatitis, eczema, vesicobullous rash, maculopapular rash, erythema multiforme. EXTRANEAL was additionally studied in subpopulation of 92 high average/high transporter APD patients in two-week controlled clinical trial where patients received single daily exchange of EXTRANEAL (n=47) or dextrose control (n=45) for the long dwell (14 +- hours). Consistent with the data reported in the original trials of EXTRANEAL, rash was the most frequently occurring event.. Clinical Laboratory Findings. An increase in mean serum alkaline phosphatase has been observed in clinical studies of ESRD patients receiving EXTRANEAL. No associated increases in other liver chemistry tests were observed. Serum alkaline phosphatase levels did not show progressive increase over 12-month study period. Levels returned to normal approximately two weeks after discontinuation of EXTRANEAL.Decreases in serum sodium and chloride have been observed in patients using EXTRANEAL. The mean change in serum sodium from baseline to the last study visit was -2.8 mmol/L for patients on EXTRANEAL and -0.3 mmol/L for patients on control solution. Four EXTRANEAL patients and two control patients developed serum sodium 125 mmol/L. The mean change in serum chloride from baseline to last study visit was -2 mmol/L for EXTRANEAL patients and 0.6 mmol/L for control patients. Similar changes in serum chemistries were observed in an additional clinical study in subpopulation of high average/high transporter patients. The declines in serum sodium and chloride may be related to dilution resulting from the presence of icodextrin metabolites in plasma.An apparent decrease in serum amylase activity has been observed in patients administered EXTRANEAL. Investigations indicate that icodextrin and its metabolites interfere with enzymatic-based amylase assays, resulting in inaccurately low values. This should be taken into account when evaluating serum amylase levels for diagnosis or monitoring of pancreatitis in patients using EXTRANEAL.. 6.2 Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of EXTRANEAL, or in conjunction with performing the peritoneal dialysis procedure. Because these reactions are reported voluntarily from population of uncertain size, it is not possible to estimate their frequency reliably or to establish causal relationship to drug exposure.INFECTIONS AND INFESTATIONS: Fungal peritonitis, Peritonitis bacterial, Catheter related infectionBLOOD AND LYMPHATIC SYSTEM DISORDERS: Thrombocytopenia, Leukopenia, LeukocytosisIMMUNE SYSTEM DISORDERS: Vasculitis, Serum sickness, HypersensitivityMETABOLISM AND NUTRITION DISORDERS: Hypoglycemic shock, DehydrationNERVOUS SYSTEM DISORDERS: Hypoglycemic coma, Burning sensationEYE DISORDERS: Vision blurredRESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Bronchospasm, StridorGASTROINTESTINAL DISORDERS: Encapsulating peritoneal sclerosis, Aseptic peritonitis, Ileus, Ascites, Inguinal herniaSKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Angioedema, Urticaria generalized, Prurigo, Dermatitis (including bullous, allergic and contact), Erythema, Onychomadesis, Dry skin, Skin chapped, BlisterMUSCULOSKELETAL, CONNECTIVE TISSUE DISORDERS: Musculoskeletal painREPRODUCTIVE SYSTEM AND BREAST DISORDERS: Penile edema, Scrotal edemaGENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS: Pyrexia, Chills, Malaise, Catheter site erythema, Catheter site inflammation, Infusion related reaction (including Infusion site pain, Instillation site pain)INVESTIGATIONS: Liver function test abnormal, Urine output decreased.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. EXTRANEAL is an isosmotic peritoneal dialysis solution containing glucose polymers (icodextrin) as the primary osmotic agent. Icodextrin functions as colloid osmotic agent to achieve ultrafiltration during long peritoneal dialysis dwells. Icodextrin acts in the peritoneal cavity by exerting osmotic pressure across small intercellular pores resulting in transcapillary ultrafiltration throughout the dwell. Like other peritoneal dialysis solutions, EXTRANEAL also contains electrolytes to help normalize electrolyte balance and lactate to help normalize acid-base status.. 12.2 Pharmacodynamics. EXTRANEAL results in reduction in the absorbed caloric (carbohydrate) load compared to 4.25% hyperosmolar glucose solutions. Additionally, EXTRANEAL results in an increased ultrafiltration volume per gram of absorbed carbohydrate compared to hyperosmolar glucose solutions.. 12.3 Pharmacokinetics. Absorption. Absorption of icodextrin from the peritoneal cavity follows zero-order kinetics consistent with convective transport via peritoneal lymphatic pathways. In single-dose pharmacokinetic study using EXTRANEAL, median of 40% (60 g) of the instilled icodextrin was absorbed from the peritoneal solution during 12-hour dwell. Plasma levels of icodextrin rose during the dwell and declined after the dwell was drained. Peak plasma levels of icodextrin plus its metabolites (median Cpeak 2.2 g/L) were observed at the end of the long dwell exchange (median Tmax 13 hours). At steady-state, the mean plasma level of icodextrin plus its metabolites was about g/L. In multi-dose studies, steady-state levels of icodextrin were achieved within one week. Plasma levels of icodextrin and metabolites return to baseline values within approximately two weeks following cessation of icodextrin administration.. Metabolism. Icodextrin is metabolized by alpha-amylase into oligosaccharides with lower degree of polymerization (DP), including maltose (DP2), maltotriose (DP3), maltotetraose (DP4), and higher molecular weight species. In single dose study, DP2, DP3 and DP4 showed progressive rise in plasma concentrations with profile similar to that for total icodextrin, with peak values reached by the end of the dwell and declining thereafter. Only very small increases in blood levels of larger polymers were observed. Steady-state plasma levels of icodextrin metabolites were achieved within one week and stable plasma levels were observed during long-term administration.Some degree of metabolism of icodextrin occurs intraperitoneally with progressive rise in the concentration of the smaller polymers in the dialysate during the 12-hour dwell.. Elimination. Icodextrin undergoes renal elimination in direct proportion to the level of residual renal function. Diffusion of the smaller icodextrin metabolites from plasma into the peritoneal cavity is also possible after systemic absorption and metabolism of icodextrin.. Special Populations. GeriatricsThe influence of age on the pharmacokinetics of icodextrin and its metabolites was not assessed.Gender and RaceThe influence of gender and race on the pharmacokinetics of icodextrin and its metabolites was not assessed.. Drug Interactions InsulinA clinical study in insulin-dependent diabetic patients demonstrated no effect of EXTRANEAL on insulin absorption from the peritoneal cavity or on insulins ability to control blood glucose when insulin was administered intraperitoneally with EXTRANEAL. However, appropriate monitoring of blood glucose should be performed when initiating EXTRANEAL in diabetic patients and insulin dosage should be adjusted if needed [see Drug Interactions (7)].HeparinIn vitro studies demonstrated no evidence of incompatibility of heparin with EXTRANEAL.AntibioticsCompatibility has been demonstrated with vancomycin, cefazolin, ceftazidime, gentamicin, and netilmicin. However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.Minimum Inhibitory Concentration (MIC)No formal clinical drug interaction studies have been performed. In vitro studies with EXTRANEAL and the following antibiotics have demonstrated no effects with regard to minimum inhibitory concentration (MIC): vancomycin, cefazolin, ampicillin, ampicillin/flucoxacillin, ceftazidime, gentamicin, and amphotericin.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience. EXTRANEAL was originally studied in controlled clinical trials of 493 patients with end-stage renal disease who received single daily exchange of EXTRANEAL for the long dwell (8-to 16- hours). There were 215 patients exposed for at least months and 155 patients exposed for at least one year. The population was 18-83 years of age, 56% male and 44% female, 73% Caucasian, 18% Black, 4% Asian, 3% Hispanic, and it included patients with the following comorbid conditions: 27% diabetes, 49% hypertension and 23% hypertensive nephropathy.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide basis for identifying the adverse events that appear to be related to drug use and for approximating rates.Rash was the most frequently occurring EXTRANEAL-related adverse reaction (5.5%, EXTRANEAL; 1.7% Control). Seven patients on EXTRANEAL discontinued treatment due to rash, and one patient on EXTRANEAL discontinued due to exfoliative dermatitis. The rash typically appeared within the first three weeks of treatment and resolved with treatment discontinuation or, in some patients, with continued treatment.Table shows the adverse events reported in these clinical studies regardless of causality, occurring in >= 5% of patients and more common on EXTRANEAL than control.Table - Adverse Experiences in >=5% of Patients and More Common on EXTRANEAL EXTRANEALControlN 493N 347Peritonitis26%25%Upper respiratory infection15%13%Hypertension13%8%Rash10%5%Headache9%7%Abdominal Pain8%6%Flu syndrome7%6%Nausea7%5%Cough increase7%4%Edema6%5%Accidental injury6%4%Chest pain5%4%Dyspepsia5%4%Hyperglycemia5%4%Adverse events related to EXTRANEAL use or in conjunction with performing the peritoneal dialysis procedure include:Reported with an incidence of 5% and at least as common on dextrose control included asthenia, exit site infection, infection, back pain, hypotension, diarrhea, vomiting, anemia, peripheral edema, hypokalemia, hyperphosphatemia, hypoproteinemia, hypervolemia, arthralgia, dizziness, dyspnea, pruritis. Reported with an incidence of 5%: pain on infusion, abdominal enlargement, cloudy effluent, ultrafiltration decrease, postural hypotension, heart failure, hyponatremia, hypochloremia, hypercalcemia, hypoglycemia, alkaline phosphatase increase, SGPT increase, SGOT increase, cramping, confusion, lung edema, facial edema, exfoliative dermatitis, eczema, vesicobullous rash, maculopapular rash, erythema multiforme. EXTRANEAL was additionally studied in subpopulation of 92 high average/high transporter APD patients in two-week controlled clinical trial where patients received single daily exchange of EXTRANEAL (n=47) or dextrose control (n=45) for the long dwell (14 +- hours). Consistent with the data reported in the original trials of EXTRANEAL, rash was the most frequently occurring event.. Clinical Laboratory Findings. An increase in mean serum alkaline phosphatase has been observed in clinical studies of ESRD patients receiving EXTRANEAL. No associated increases in other liver chemistry tests were observed. Serum alkaline phosphatase levels did not show progressive increase over 12-month study period. Levels returned to normal approximately two weeks after discontinuation of EXTRANEAL.Decreases in serum sodium and chloride have been observed in patients using EXTRANEAL. The mean change in serum sodium from baseline to the last study visit was -2.8 mmol/L for patients on EXTRANEAL and -0.3 mmol/L for patients on control solution. Four EXTRANEAL patients and two control patients developed serum sodium 125 mmol/L. The mean change in serum chloride from baseline to last study visit was -2 mmol/L for EXTRANEAL patients and 0.6 mmol/L for control patients. Similar changes in serum chemistries were observed in an additional clinical study in subpopulation of high average/high transporter patients. The declines in serum sodium and chloride may be related to dilution resulting from the presence of icodextrin metabolites in plasma.An apparent decrease in serum amylase activity has been observed in patients administered EXTRANEAL. Investigations indicate that icodextrin and its metabolites interfere with enzymatic-based amylase assays, resulting in inaccurately low values. This should be taken into account when evaluating serum amylase levels for diagnosis or monitoring of pancreatitis in patients using EXTRANEAL.

DESCRIPTION SECTION.

11 DESCRIPTION. EXTRANEAL (icodextrin) Peritoneal Dialysis Solution is solution intended for intraperitoneal administration that contains the colloid osmotic agent icodextrin. Icodextrin is starch-derived, water-soluble glucose polymer linked by alpha (1-4) and less than 10% alpha (1-6) glucosidic bonds with weight-average molecular weight between 13,000 and 19,000 Daltons and number average molecular weight between 5,000 and 6,500 Daltons. The representative structural formula of icodextrin is:Each 100 mL of EXTRANEAL contains: Icodextrin 7.5 Sodium Chloride, USP535 mgSodium Lactate448 mgCalcium Chloride, USP25.7 mgMagnesium Chloride, USP5.08 mgElectrolyte content per liter: Sodium 132 mEq/L Calcium3.5 mEq/LMagnesium0.5 mEq/LChloride96 mEq/LLactate40 mEq/LWater for Injection, USP qsHCl/NaOH may have been used to adjust pH.EXTRANEAL contains no bacteriostatic or antimicrobial agents.Calculated osmolarity: 282-286 mOsm/L; pH=5.0-6.0EXTRANEAL is sterile, nonpyrogenic, clear solution packaged in flexible container systems that are composed of polyvinyl chloride.Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to parts per million; however, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.. Image of Structural Formula of Icodextrin.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intraperitoneal administration only. Not for intravenous or intra-arterial administration. Administer as single daily peritoneal dialysis (PD) exchange for the long dwell. Dosage should be individualized by the prescribing physician experienced in the treatment of end-stage renal disease with PD. (2.1). 2.1 Basic Dosing Information. EXTRANEAL is intended for intraperitoneal administration only. Not for intravenous or intra-arterial administration. Administer as single daily exchange for the long dwell in continuous ambulatory peritoneal dialysis or automated peritoneal dialysis. The recommended dwell time is 8- to 16- hours. Administer over period of 10-20 minutes at rate that is comfortable for the patient.The mode of therapy, frequency of treatment, exchange volume, duration of dwell, and length of dialysis should be initiated and supervised by the prescribing physician experienced in the treatment of end-stage renal disease with peritoneal dialysis. It is recommended that patients being placed on peritoneal dialysis should be appropriately trained in program that is under supervision of physician.. 2.2 Directions for Use. For complete CAPD and APD system preparation, see directions accompanying ancillary equipment.Aseptic technique should be used throughout the peritoneal dialysis procedure.For single-dose only.. Storage. Store in moisture barrier overwrap and in carton until ready to use [see How Supplied/Storage and Handling (16)].. Warming. For patient comfort, EXTRANEAL can be warmed to 37C (98.6F). Only dry heat should be used (e.g., heating pad, warming plate). Do not immerse EXTRANEAL in water for warming. Do not use microwave oven to warm EXTRANEAL. Do not heat above 40C (104F).. To Open. To open, tear the overwrap down at the slit and remove the solution container. Some opacity of the plastic, due to moisture absorption during the sterilization process, may be observed. This does not affect the solution quality or safety and may often leave slight amount of moisture within the overwrap.. Inspect for Container Integrity and Solution Appearance. Do not use EXTRANEAL if it is cloudy or discolored, if it contains particulate matter, or if the container is leaking.Inspect the patient connector to ensure the pull ring is attached. Do not use if pull ring is not attached to the connector. Inspect the EXTRANEAL container for signs of leakage and check for minute leaks by squeezing the container firmly. If the container has frangible(s), inspect that they are positioned correctly and are not broken. Do not use EXTRANEAL if the frangible(s) are broken or leaks are suspected as sterility may be impaired.For EXTRANEAL in ULTRABAG, inspect the tubing and drain container for presence of solution. Small droplets are acceptable, but if solution flows past the frangible prior to use, do not use and discard the units.. Adding Medications. The decision to add medication should be made by the physician after careful evaluation of the patient [see Drug Interactions (7), Clinical Pharmacology (12.3)].If the re-sealable rubber plug on the medication port is missing or partly removed, do not use the product.To add medication:1.Put on mask. Clean and/or disinfect hands.2.Prepare medication port site using aseptic technique.3.Using syringe with 1-inch long, 25- to 19-gauge needle, puncture the medication port and inject additive.4.Reposition container with container ports up and evacuate medication port by squeezing and tapping it.5.Mix solution and additive thoroughly.. 1.Put on mask. Clean and/or disinfect hands.. 2.Prepare medication port site using aseptic technique.. 3.Using syringe with 1-inch long, 25- to 19-gauge needle, puncture the medication port and inject additive.. 4.Reposition container with container ports up and evacuate medication port by squeezing and tapping it.. 5.Mix solution and additive thoroughly.. Preparation for Administration. 1.Put on mask. Clean and/or disinfect hands.2.Place EXTRANEAL on work surface.3.For CAPD manual exchanges using ULTRABAG, uncoil tubing and drain bag. Ensure the patient transfer set is closed. Break the connector (Y-set) frangible.4.Remove pull ring from connector of solution container. If continuous fluid flow from connector is observed, discard solution container. Once the pull ring has been removed, do not reuse the solution or container.5.Immediately attach the solution container to patient connector (transfer set) or appropriate peritoneal dialysis set.6.For APD therapy using AMBU-FLEX II Plastic Container with Pull Ring Cap, continue with therapy set-up as instructed in user manual or directions accompanying tubing sets for automated peritoneal dialysis.7.For ULTRABAG, follow the below steps:oClamp solution line and then break frangible near solution bag. Hang solution container and place the drainage container below the level of the abdomen.oOpen transfer set to drain the solution from abdomen. If drainage cannot be established, contact your clinician. When drainage complete, close transfer set.oRemove clamp from solution line and flush new solution to flow into the drainage container for seconds to prime the line. Clamp drain line after flush complete.oOpen transfer set to fill. When fill complete, close transfer set and clamp solution line.oPut on mask. Clean and/or disinfect hands.oDisconnect ULTRABAG from transfer set and apply MINICAP.Completion of Therapy1.Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis.2.Discard unused portion.. 1.Put on mask. Clean and/or disinfect hands.. 2.Place EXTRANEAL on work surface.. 3.For CAPD manual exchanges using ULTRABAG, uncoil tubing and drain bag. Ensure the patient transfer set is closed. Break the connector (Y-set) frangible.. 4.Remove pull ring from connector of solution container. If continuous fluid flow from connector is observed, discard solution container. Once the pull ring has been removed, do not reuse the solution or container.. 5.Immediately attach the solution container to patient connector (transfer set) or appropriate peritoneal dialysis set.. 6.For APD therapy using AMBU-FLEX II Plastic Container with Pull Ring Cap, continue with therapy set-up as instructed in user manual or directions accompanying tubing sets for automated peritoneal dialysis.. 7.For ULTRABAG, follow the below steps:. oClamp solution line and then break frangible near solution bag. Hang solution container and place the drainage container below the level of the abdomen.. oOpen transfer set to drain the solution from abdomen. If drainage cannot be established, contact your clinician. When drainage complete, close transfer set.. oRemove clamp from solution line and flush new solution to flow into the drainage container for seconds to prime the line. Clamp drain line after flush complete.. oOpen transfer set to fill. When fill complete, close transfer set and clamp solution line.. oPut on mask. Clean and/or disinfect hands.. oDisconnect ULTRABAG from transfer set and apply MINICAP.. 1.Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis.. 2.Discard unused portion.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. EXTRANEAL (icodextrin) is indicated for single daily exchange for the long (8- to 16- hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of end-stage renal disease. EXTRANEAL is also indicated to improve (compared to 4.25% dextrose) long-dwell ultrafiltration and clearance of creatinine and urea nitrogen in patients with high average or greater transport characteristics, as defined using the peritoneal equilibration test (PET) [see Clinical Pharmacology (12), Clinical Studies (14)]. oFor single daily exchange for the long (8- to 16- hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of end-stage renal disease. (1)oTo improve (compared to 4.25% dextrose) long-dwell ultrafiltration and clearance of creatinine and urea nitrogen in patients with high average or greater transport characteristics, as defined using the peritoneal equilibration test (PET). (1). oFor single daily exchange for the long (8- to 16- hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of end-stage renal disease. (1). oTo improve (compared to 4.25% dextrose) long-dwell ultrafiltration and clearance of creatinine and urea nitrogen in patients with high average or greater transport characteristics, as defined using the peritoneal equilibration test (PET). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Inform patients of the following:oOnly use glucose-specific glucose monitoring systems when measuring blood glucose. Falsely elevated blood glucose readings have led patients or health care providers to withhold treatment of hypoglycemia or to administer insulin inappropriately. oSerious allergic reactions have been observed in patients using EXTRANEAL. Patients should call their doctor or get medical help if they experience any of these symptoms during treatment with EXTRANEAL: swelling of the face, eyes, lips, tongue, or mouth; trouble swallowing or breathing; skin rash, hives, sores in the mouth, on eyelids, or in the eyes; or, if skin blisters or peels.oPeritonitis is common side effect of patients on peritoneal dialysis. Symptoms of peritonitis may include cloudy peritoneal effluent, pain, erythema or drainage at the exit site, or fever.Because patients self-administer EXTRANEAL at home, patients should also be instructed to:oFollow the peritoneal dialysis (PD) training instructions given by the health care provider. Use aseptic technique throughout their entire PD procedure. Discard any unused EXTRANEAL solution [see Dosage and Administration (2.2)].oCheck the appearance of EXTRANEAL solution prior to use. Do not use EXTRANEAL if solution appears cloudy, discolored, contain visible particulate matter, or if there is evidence of leaking containers.oRegularly check fluid balance and body weight to avoid over-hydration or dehydration and associated side effects.oInform their physicians about any changes in prescription or over-the-counter medications and supplements.oHave periodic laboratory tests and routinely follow up with their health care provider.oIn case of damage, the container should be discarded. oOnly use glucose-specific glucose monitoring systems when measuring blood glucose. Falsely elevated blood glucose readings have led patients or health care providers to withhold treatment of hypoglycemia or to administer insulin inappropriately. oSerious allergic reactions have been observed in patients using EXTRANEAL. Patients should call their doctor or get medical help if they experience any of these symptoms during treatment with EXTRANEAL: swelling of the face, eyes, lips, tongue, or mouth; trouble swallowing or breathing; skin rash, hives, sores in the mouth, on eyelids, or in the eyes; or, if skin blisters or peels.. oPeritonitis is common side effect of patients on peritoneal dialysis. Symptoms of peritonitis may include cloudy peritoneal effluent, pain, erythema or drainage at the exit site, or fever.. oFollow the peritoneal dialysis (PD) training instructions given by the health care provider. Use aseptic technique throughout their entire PD procedure. Discard any unused EXTRANEAL solution [see Dosage and Administration (2.2)].. oCheck the appearance of EXTRANEAL solution prior to use. Do not use EXTRANEAL if solution appears cloudy, discolored, contain visible particulate matter, or if there is evidence of leaking containers.. oRegularly check fluid balance and body weight to avoid over-hydration or dehydration and associated side effects.. oInform their physicians about any changes in prescription or over-the-counter medications and supplements.. oHave periodic laboratory tests and routinely follow up with their health care provider.. oIn case of damage, the container should be discarded.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL. Container LabelL5B4974NDC 0941-0679-062000 mL(APPROX 80 mL EXCESS)BaxterExtraneal (icodextrin)Peritoneal Dialysis SolutionEACH 100 mL CONTAINS 7.5 ICODEXTRN 535 mgSODIUM CHLORIDE USP 448 mg SODIUM LACTATE25.7 mg CALCIUM CHLORIDE USP 5.08 mg MAGNESIUMCHLORIDE USP WATER FOR INJECTION USPmEq/L SODIUM 132 CALCIUM 3.5 MAGNESIUM 0.5 CHLORIDE 96 LACTATE 40pH 5.0 6.0 pH MAY HAVE BEEN ADJUSTED WITHHYDROCHLORIC ACID OR SODIUM HYDROXIDEEXTRANEAL SOLUTION CONTAINS NO BACTERIOSTATIC ORANTIMICROBIAL AGENTSOSMOLARITY (CALC) 282 286 mOsmol/LSTERILE NONPYROGENICPOTASSIUM CHLORIDE TO BE ADDED ONLY UNDERTHE DIRECTION OF PHYSICIANSEE PACKAGE INSERT FOR DOSAGE INFORMATIONUSE AS DIRECTED BY PHYSICIANFOR INTRAPERITONEAL ADMINISTRATION ONLYCAUTIONS SQUEEZE AND INSPECT INNER BAGTHAT MAINTAINS PRODUCT STERILITY DISCARD IFLEAKS ARE FOUNDDO NOT USE UNLESS SOLUTION IS CLEARDISCARD UNUSED PORTIONRx ONLYSTORE IN MOISTURE BARRIER OVERPOUCH IN CARTONUNTIL READY TO USESTORE AT 20-25C (68-77F) EXCURSIONS PERMITTEDTO 15-30C (59-86F) [SEE USP CONTROLLED ROOMTEMPERATURE] PROTECT FROM FREEZINGAmbu-Flex II CONTAINERPL 146 PLASTICBAXTER EXTRANEAL AMBU-FLEX II AND PL 146 ARETRADEMARKS OF BAXTER INTERNATIONAL INCBAXTER HEALTHCARE CORPORATION DEERFIELD IL 60015 USAMADE IN USAUS PAT NOS 4761237 4886789 6077836 6248726 B1Bar Code (01) 00309410679067PD-2 7.5% icodextrin. Extraneal Representative Container Label NDC 0941-0679-06.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption. Absorption of icodextrin from the peritoneal cavity follows zero-order kinetics consistent with convective transport via peritoneal lymphatic pathways. In single-dose pharmacokinetic study using EXTRANEAL, median of 40% (60 g) of the instilled icodextrin was absorbed from the peritoneal solution during 12-hour dwell. Plasma levels of icodextrin rose during the dwell and declined after the dwell was drained. Peak plasma levels of icodextrin plus its metabolites (median Cpeak 2.2 g/L) were observed at the end of the long dwell exchange (median Tmax 13 hours). At steady-state, the mean plasma level of icodextrin plus its metabolites was about g/L. In multi-dose studies, steady-state levels of icodextrin were achieved within one week. Plasma levels of icodextrin and metabolites return to baseline values within approximately two weeks following cessation of icodextrin administration.. Metabolism. Icodextrin is metabolized by alpha-amylase into oligosaccharides with lower degree of polymerization (DP), including maltose (DP2), maltotriose (DP3), maltotetraose (DP4), and higher molecular weight species. In single dose study, DP2, DP3 and DP4 showed progressive rise in plasma concentrations with profile similar to that for total icodextrin, with peak values reached by the end of the dwell and declining thereafter. Only very small increases in blood levels of larger polymers were observed. Steady-state plasma levels of icodextrin metabolites were achieved within one week and stable plasma levels were observed during long-term administration.Some degree of metabolism of icodextrin occurs intraperitoneally with progressive rise in the concentration of the smaller polymers in the dialysate during the 12-hour dwell.. Elimination. Icodextrin undergoes renal elimination in direct proportion to the level of residual renal function. Diffusion of the smaller icodextrin metabolites from plasma into the peritoneal cavity is also possible after systemic absorption and metabolism of icodextrin.. Special Populations. GeriatricsThe influence of age on the pharmacokinetics of icodextrin and its metabolites was not assessed.Gender and RaceThe influence of gender and race on the pharmacokinetics of icodextrin and its metabolites was not assessed.. Drug Interactions InsulinA clinical study in insulin-dependent diabetic patients demonstrated no effect of EXTRANEAL on insulin absorption from the peritoneal cavity or on insulins ability to control blood glucose when insulin was administered intraperitoneally with EXTRANEAL. However, appropriate monitoring of blood glucose should be performed when initiating EXTRANEAL in diabetic patients and insulin dosage should be adjusted if needed [see Drug Interactions (7)].HeparinIn vitro studies demonstrated no evidence of incompatibility of heparin with EXTRANEAL.AntibioticsCompatibility has been demonstrated with vancomycin, cefazolin, ceftazidime, gentamicin, and netilmicin. However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.Minimum Inhibitory Concentration (MIC)No formal clinical drug interaction studies have been performed. In vitro studies with EXTRANEAL and the following antibiotics have demonstrated no effects with regard to minimum inhibitory concentration (MIC): vancomycin, cefazolin, ampicillin, ampicillin/flucoxacillin, ceftazidime, gentamicin, and amphotericin.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oUse glucose-specific glucose monitoring systems when measuring blood glucose (5.1)oEncapsulating peritoneal sclerosis (5.2)oPeritonitis: Initiate appropriate antimicrobial therapy. (5.2)oHypersensitivity reactions: Serious reactions have been reported. Discontinue use of EXTRANEAL if serious reaction is suspected. (5.3)oMonitor for lactic acidosis in patients at risk (5.4)oMonitor for electrolyte, fluid, and nutrition imbalances (5.6). oUse glucose-specific glucose monitoring systems when measuring blood glucose (5.1). oEncapsulating peritoneal sclerosis (5.2). oPeritonitis: Initiate appropriate antimicrobial therapy. (5.2). oHypersensitivity reactions: Serious reactions have been reported. Discontinue use of EXTRANEAL if serious reaction is suspected. (5.3). oMonitor for lactic acidosis in patients at risk (5.4). oMonitor for electrolyte, fluid, and nutrition imbalances (5.6). 5.1 Unrecognized Hypoglycemia Resulting From Drug-Device Interaction. When measuring blood glucose levels in patients using EXTRANEAL (icodextrin) Peritoneal Dialysis Solution, do not use blood glucose monitoring devices using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)-, glucose-dye-oxidoreductase (GDO)-, and some glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD)-based methods because these systems may result in falsely elevated glucose readings (due to the presence of maltose). Falsely elevated glucose readings have led patients or health care providers to withhold treatment of hypoglycemia or to administer insulin inappropriately leading to unrecognized hypoglycemia. Falsely elevated glucose levels may be measured up to two weeks following cessation of EXTRANEAL (icodextrin) therapy when GDH-PQQ, GDO, and GDH-FAD-based blood glucose monitors and test strips are used.Additionally, other glucose-measuring technologies, such as continuous glucose monitoring systems, may or may not be compatible with EXTRANEAL. Always contact the device manufacturer for current information regarding compatibility and intended use of the device in the dialysis patient population. For additional information, please contact the Baxter Renal Clinical Help Line 1-888-RENAL-HELP or visit www.glucosesafety.com.. 5.2 Peritonitis and Encapsulating Peritoneal Sclerosis. Infectious and aseptic peritonitis has been associated with EXTRANEAL use. Following EXTRANEAL use, inspect the drained fluid for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis. Improper clamping or priming sequence may result in infusion of air into the peritoneal cavity, which may result in abdominal pain and/or peritonitis. If peritonitis occurs, treat with appropriate therapy.Encapsulating peritoneal sclerosis (EPS), sometimes fatal, is complication of peritoneal dialysis therapy and has been reported in patients using EXTRANEAL.. 5.3 Hypersensitivity Reactions. Serious hypersensitivity reactions to EXTRANEAL have been reported such as toxic epidermal necrolysis, angioedema, serum sickness, erythema multiforme and vasculitis [see Adverse Reactions 6.1 6.2 )]. Anaphylactic or anaphylactoid reactions may occur. Stop the infusion immediately and drain the solution from the peritoneal cavity if any signs or symptoms of suspected hypersensitivity reaction develop. Institute appropriate therapeutic countermeasures as clinically indicated.. 5.4 Lactic Acidosis. Monitor patients with conditions known to increase the risk of lactic acidosis [e.g., severe hypotension or sepsis that can be associated with acute renal failure, inborn errors of metabolism, treatment with drugs such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] for lactic acidosis before the start of treatment and during treatment with EXTRANEAL [see Contraindications 4.3)].. 5.5 Overinfusion. Overinfusion of peritoneal dialysis solution volume into the peritoneal cavity may be characterized by abdominal distention, feeling of fullness and/or shortness of breath. Drain the peritoneal dialysis solution from the peritoneal cavity to treat overinfusion.. 5.6 Electrolyte, Fluid, and Nutrition Imbalances. Peritoneal dialysis may affect patients protein, water-soluble vitamin, potassium, sodium, chloride, bicarbonate, and magnesium levels and volume status [see Adverse Reactions 6 )]. Monitor electrolytes and blood chemistry periodically and take appropriate clinical action. Potassium is omitted from EXTRANEAL solutions because dialysis may be performed to correct hyperkalemia. In situations where there is normal serum potassium level or hypokalemia, the addition of potassium chloride (up to concentration of mEq/L) may be indicated to prevent severe hypokalemia. Monitor fluid status to avoid hyper- or hypovolemia and potentially severe consequences including congestive heart failure, volume depletion, and hypovolemic shock.